Material and method for treating internal cavities

ABSTRACT

A method of providing sustained-release topical treatment of a condition affecting an internal body cavity is provided. The method comprises administering a pharmaceutical composition comprising a thermoreversible hydrogel and an active pharmaceutical ingredient to an internal body cavity of the urinary tract. After administration, the concentration of the active pharmaceutical ingredient in urothelium of the internal body cavity is increased when compared to the concentration of the active pharmaceutical ingredient in urothelium of the internal body cavity following administration of a control composition comprising the same dose and concentration of active pharmaceutical ingredient in water.

REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. patent application Ser. No.17/566,882, filed Dec. 31, 2021, which is a Continuation of U.S. patentapplication Ser. No. 16/518,511, filed Jul. 22, 2019, which is aContinuation of U.S. patent application Ser. No. 14/054,731, filed Oct.15, 2013, now U.S. Pat. No. 10,471,150, which is a Continuation-in-Partof U.S. patent application Ser. No. 13/553,198, filed Jul. 19, 2012, nowU.S. Pat. No. 9,040,074, which is a Continuation-in-Part ofInternational (PCT) Patent Application No. PCT/IL2011/000069, filed Jan.20, 2011, which claims priority from U.S. Provisional Patent ApplicationNo. 61/296,589, filed Jan. 20, 2010, each of which are herebyincorporated by reference in their entireties.

FIELD OF THE INVENTION

The invention relates in general to materials, means and methods forsustained release of therapeutic agents for topical treatments. Itrelates in particular to means and methods for topical treatment ofdiseases of internal body cavities by embedding therapeutic agents in aslowly degrading biocompatible mixture applied to affected tissue.

BACKGROUND OF THE INVENTION

i. Internal Cavities

Internal body cavities (e.g., cavities within the body accessiblethrough a body orifice or via image guided laparoscopic methods) containorgans that when diseased may benefit from prolonged topical exposure tocertain drugs. These cavities are naturally wet and are eithercontinuously flushed or generate a flow of body fluids, such as urine,serous fluids or lymphatic fluids—that contribute to gradual expellingof treatment materials.

Many cavities are characterized by their internal natural movement—due,for example, to body motion or peristaltic motion—that constantlychanges their shape.

The tissue in all internal cavities in the body is composed of onlythree basic types of tissue: epithelial, connective and muscular. Almostall epithelial cells, rest on connective tissue, the lamina propria,which support the epithelium and provides nutrition and binds toneighboring structures. The common types of covering epithelia can haveeither simple, pseudo-stratified or stratified cell structure. Theepithelia of vessels and serous cavities are squamous, but many othercavities have epithelia cell structure that is either cuboidal orcolumnar, which provide good mechanical protection and good ability toachieve adhesion. The mouth, esophagus, larynx, vagina and anal canalhave a non-keratinized cell structure to maintain wetness and are morechallenging for adhesion, The urinary tract has similar, buttransitional cell structure, that provides stretching, mechanicalstrength and strongest resistance to adhesion of materials.

Several common tissue properties affect the requirements for targeteddelivery materials:

-   -   wetness of the cavity lining tissue    -   mechanical composition and consistency    -   absorption capability    -   expansion and movement characteristics of the internal cavities        or attached organs    -   existence of body fluids for expelling the delivery materials        ii. Topical Treatment of Diseases

The method by which a drug is delivered can have a significant effect onits efficacy. In many cases, the drug is introduced into the bloodsystem, which then delivers it via the blood stream throughout the body.This form of access is broadly termed systemic treatment. In othercases, a more targeted delivery can focus the therapeutic effect ontothe target organ, providing therapeutic benefits and avoiding sideeffects. Some drugs have an optimum concentration range within whichmaximum benefit is derived, and concentrations above or below this rangecan be toxic or produce no therapeutic benefit at all. In the context ofthe present invention, treatments that effect specific tissues or organsby directly accessing them are termed topical treatments, as opposed tosystemic treatments that were described above. Sustained release of adrug involves polymers that typically release the drug at a controlledrate due to diffusion out of the polymer or by dilution of the polymerover time. Topical administration of drugs changes the rate at whichdrugs enter the tissue and the pharmacokinetics of the drug, thus thecorrectly designed materials can optimize the therapeutic effect bycontrolling the drug release rate. Since all internal organ tissue iswater-based, administering drugs in water-based solutions is optimal.

iii. Topically Administered Drugs

Among the drugs that can be administered topically are drugs that belongto the following families:

-   -   1. Antineoplastic drugs    -   2. Chemotherapeutic agents    -   3. Anti-infective agents (e.g. Antimicrobial drugs,        Antiparasitic agents, Antivirals)    -   4. Genito-urinary system drugs    -   5. Anti-inflammatory products    -   6. Analgesics    -   7. Musculoskeletal system acting drugs    -   8. Drugs acting on the blood and blood forming organs        (Antihemorrhagics, Antithrombotic agents, antianemic drugs)    -   9. Dermatologic drugs (antifungals, antiseptic)    -   10. Gastrointestinal system (antiobesity, acid related        disorders(    -   11. Metabolism drugs    -   12. Neurological drugs    -   13. Respiratory drugs including nasal drugs    -   14. Cardio-vascular drugs    -   15. Otological drugs    -   16. Anti-infective drugs    -   17. Corticosteroids drugs    -   18. Analgesics drugs    -   19. Antiparasitics drugs    -   20. Anasthetic Drugs

In other cases, the topical treatment is just evolving:

-   -   21. Growth factor (e.g., for treatment of heart muscle ischemia)    -   22. Gene Therapy agents        In other cases, the topically administered material has medical        effect without actually being considered an active        pharmaceutical ingredient:    -   23. Mucin    -   24. Hyaluronic Acid        Besides their therapeutic effect, drugs are classified according        to their chemical and physical properties and thus constitute        families of compounds that, due to their common similar        characteristics, fit particular drug vehicles. Some of those        properties include:    -   Lipophilicity or hydrophilicity    -   Molecular weight and physical size    -   Diffusability through different media which is hydrophobic,        hydrophilic, viscose, etc.    -   Solubility        iv. Physical Characteristics of Internal Cavities

The effectiveness of application of a topical therapeutic agent to aspecific internal cavity will depend on the physical characteristics ofthe inner tissue of that internal cavity, in particular, characteristicssuch as:

-   -   Access—ease of introducing liquid or gel into the cavity    -   Tissue type that defines adhesiveness—ability to attach reliably        and consistently polymer to the cavity tissue    -   Internal movement—effected by gravitational motion, stretching,        peristaltic motion, etc. that cause periodical changes in the        shape and volume of the cavity—pressure and volume regime    -   Wetness—to enable diffusion of drugs into the tissue    -   Degradability mechanism—flow of liquids or aqueous solutions,        e.g. urine, serous or lymphatic fluids,

The specific values of cavity characteristics require carefulconsideration in the development of topical drugs suitable for treatmentof diseases inside these cavities.

Table 1 summarizes the different organs, types of tissue their innerlining is made of and characteristics of the surrounding medium.

TABLE 1 Type of Elasticity/ System Organ Tissue Mobility pH SurroudingsDigestive Mouth/Tongue Mucosal Very Neutral Flow of food and liquidsEsophagus Mucosal None Neutral Flow of food and liquids Stomach MucosalVery Strongly Very acidic fluids, enzimatic acidic activity DuodenumMucosal Moderate Slightly Flow of bolus, enzymatic activity alakineSmall intestine Mucosal, Moderate Slightly Flow of bolus, enzymaticciliated alakine activity, absorption of nutrients Large intestineMucosal Moderate Slightly Flow of feces alakine Rectum Mucosal ModerateSlightly Flow of feces alakine Respiratory Mouth/Nose Mucosal NoneNeutral Flow of air and humidity Larinx Mucosal Moderate Neutral Flow ofair and humidity Eustachian Mucosal, None Neutral Presence of air,humidity tubes ciliated Pharinx Mucosal Moderate Neutral Flow of air andhumidity Thrachea Mucosal None Neutral Flow of air and humidityLungs/Alveoli Mucosal Moderate Neutral Flow of air and humidity UrinaryKidneys Mucosal None Slightly Blood filtration, production of acidicurine Ureters Mucosal None Slightly Flow of urine acidic Bladder MucosalVery Slightly Accumulation and evacuation of acidic urine ProstateMucosal None Slightly Flow of urine and semen (slightly acidic alkalinein ejaculation) Urethra Mucosal Moderate Slightly Flow of urine andsemen (in the acidic males) Genital Vas deferens Mucosal, None NeutralFlow of seminal fluids ciliated Epididymis Mucosal, None Neutral Flow ofseminal fluids ciliated Testes Mucosal Moderate Neutral Production ofseminal fluids Vagina Mucosal None Neutral Coitus, flow of semen, flowof menstrual fluids Cervix Mucosal Moderate Neutral Flow of semen, flowof menstrual fluids Fallopian Mucosal, None Neutral Flow of semen, flowof menstrual tubes ciliated fluids Ovules Mucosal None NeutralProduction of ova Pleura Pleural Serous Moderate Neutral Pleural fluidsmembranes Peritoneum Peritoneal Serous Moderate Neutral Peritunealfluids membranes

Disorders of the urothelium that result in Urinary Incontinence (UI)affect 200 million people worldwide. The United States NIH (NationalInstitutes of Health) has estimated that as many as 25 million adultAmericans have experienced or will experience transient or chronic UI.The NAFC (National Association of Continence) estimates that 75-80% ofthose sufferers are women, 9-13 million of whom have bothersome, severe,symptoms. It has been estimated that one in four women over the age of18 experiences episodes of involuntary leakage of urine. One-third ofmen and women aged 30-70 have experienced loss of bladder control atsome point in their adult lives and may be still living with thesymptoms. Of men and women ages 30-70 who awaken during the night to usethe bathroom, more than one-third get up twice or more per night tourinate, fitting the clinical diagnosis of nocturia. Of these adults,one in eight report they sometimes lose urine on the way to thebathroom. Overactive bladder (OAB) is especially common in older adults.It affects an estimated 1 in 11 adults in the United States. Additionalcommon disorder of the urothelium is Interstitial Cystitis (IC), achronic inflammation of the bladder that causes chronic pain anddiscomfort effecting 4 million people in the U.S. Current availabletreatment options for OAB are: bladder training; pelvic floor exercises;administration of drugs such as anti-cholinergics, capsaicin, andintravesical botulinum toxin injections; and, in severe cases, bladderaugmentation surgery.

The main shortcomings of orally-administered drugs in current use aretheir high adverse event rate resulting in patients' intolerability.Alternative routes of administration with lower adverse event rates,such as transdermal, and via suppository, have been developed. Bladderinstillation of antimuscarines also has a lower adverse event rate thanoral administration, but suffers from the disadvantage that it requiresrecurring catheterization due to the relatively short half-life of theantimuscarines, thus reducing compliance.

v. Chemotherapy—Anticancer Drugs

Many chemotherapy (antineoplastic) drugs used as cancer treatments bindto DNA, resulting in synthesis inhibition and strand breakage. Instandard intravesical instillations, chemotherapy drugs are administeredat dose concentrations of around 1 mg/ml for 1-2 hour sessions.

In the particular case of treatment of bladder cancer, the bladdertissue penetration by chemotherapy drugs—a critical parameter intreatment effectiveness—exhibits a linear relationship with theconcentration of the chemotherapy drugs (see Gao X, Au J L, Badalament RA, Wientjes M G. Bladder tissue uptake of mitomycin C duringintravesical therapy is linear with drug concentration in urine. ClinCancer Res. 1998 January; 4(1):139-43)). Furthermore, chemotherapy drugpenetration is 40% higher in the tumor tissue than in the adjacentnormal urothelium. Gao et al demonstrated double Mitomycin C (MMC)concentration in tissue when installing 40 mg/20 ml as compared with 20mg/20 ml MMC: human bladder tumors had a significantly higher tissueuptake of MMC than the normal bladder tissue.

The anti-tumor effect of chemotherapy drugs depends on concentration andexposure time. Schmittgen et al (see Schmittgen T D, Wientjes M G,Badalament R A, Au J L. Pharmacodynamics of mitomycin C in culturedhuman bladder tumors. Cancer Res. 1991 Aug. 1; 51(15):3849-56)demonstrated, both in TCC cell cultures and human bladder tumor tissuecultures, that a ten times higher concentration was needed in order toget a similar cell kill effect when exposure time to MMC was reducedfrom 24 hours to two hours.

The proven conclusion is that maintaining higher drug concentration forlonger treatment duration will enhance the treatment efficacy.

vi. Required Properties for Topical Treatment in the Bladder and OtherInternal Cavities

One approach to treatment of diseases of internal body cavities such asthe bladder is topical application of a therapeutic agent entrained in asuitable matrix/mixture. The properties of the materials to be used insuch a matrix/mixture must be adapted to the needed medical effect.Important properties include:

-   -   Rheological properties (viscosity, thixotropy, G′, G″)—required        for the introduction of the material into the internal cavity    -   Adhesion—required to coat dependably the target tissue    -   Flexibility—to comply with the volume and shape natural changes        of the internal cavity under treatment    -   Dilution in aqueous solution—to enable API release and natural        expelling of the material through body fluids    -   Mechanical properties, such as hardness, tensile strength to        provide    -   Duration of time that the material remains in the internal        cavity before it degrades    -   A suitable Active Pharmaceutical Ingredient (API)—the medical        drug or drug derivative chosen from the families listed in        section iii    -   Loading of drug or API in the material. For certain clinical        protocol the amount and concentration of the drug or API mixed        into the material have to be set to a prescribed level. The        amount of therapeutic agent thus used can be significantly lower        than used in regular parallel instillations and more than a        single API can be loaded. So the API part of the administered        material may vary from zero concentration (gel only) to 50%        (e.g., for DMSO).    -   The ability of the matrix/mixture to release the drug in a        controlled manner such that the actual drug concentration        vis-à-vis the organ tissue or lining upon which the mixture is        adhered will be optimal for each treatment. It is precisely the        specific composition of the mixture that determines the release        profile of the drug and its adsorption into the target tissue.        For example, if the API is lipophilic, the addition of certain        surface-active agents in given concentrations will provide for        their emulsification, easier release from the drug composition        and easier absorption by the internal organ lining.    -   Drug viability. The material is designed and tested not to        reduce the viability duration of the drug or API that is mixed        into it, so that the amount that is released throughout the        treatment will have the optimal therapeutic effect.        vii. Limitations of Superficial Bladder Cancer (SBC) Treatments        Known in the Art

SBC is a highly-recurrent form of cancer. To lower recurrence, it isconsidered necessary to treat patients with a single intravesicalchemotherapy instillation immediately after TUR-T.

A meta-analysis of 7 randomized trials (1,476 patients with a medianfollow-up of 3.4 years) has demonstrated that one chemotherapyinstillation immediately after Tumor resection (TUR) decreases therelative risk of recurrence by 40% (see Sylvester R J, Oosterlinck W,van der Meij den A P. A single immediate postoperative instillation ofchemotherapy decreases the risk of recurrence in patients with stage TaTi bladder cancer: a meta-analysis of published results of randomizedclinical trials. J Urol. 2004 June; 171(6 Pt 1):2186-90). The timing ofthe instillation is crucial: in all studies, instillation wasadministered within 24 hours. A study reported that if the firstinstillation was not given within 24 hours, the risk of recurrenceincreased twofold (see Kaasinen E, Rintala E, Hellström P, Viitanen J,Juusela H, Rajala P, Korhonen H, Liukkonen T; FinnBladder Group. Factorsexplaining recurrence in patients undergoing chemoimmunotherapy regimensfor frequently recurring superficial bladder carcinoma. Eur Urol. 2002August; 42(2):167-74).

Following resection and first immediate treatment patients need to bestratified by their risk for tumor progression and recurrence:

-   -   Patients with low risk for disease progression/recurrence        (30%)—need no further instillations.    -   Intermediate risk patients (40-50%)—usually receive 6 additional        sessions of Mitomycin C (MMC) chemotherapy instillations.    -   High risk patients (20%)—are treated with 6 intravesical        Bacillus Calmette-Guerin (BCG) instillations.

The efficacy of the current standard topical chemotherapy treatment forSuperficial Bladder Cancer (intravesical instillation) is limited,because there is no control on the chemotherapy concentration and thetime until it is expelled. In an attempt to prolong the standardtreatment to two hours, some physicians dictate behavioral conditions toreduce acidity of the bladder, to reduce the volume of urine before theinstillation and instill maximal concentration of chemotherapy dissolvedin minimal volume of saline.

There are several obstacles and complications known that accompany thepresently used methods for coating the internal wall of the bladder (andhence for topical treatments for bladder cancer):

-   -   The mucosal membrane. One of the physiological purposes of the        mucosal membrane that covers the bladder's inner wall, which is        permanently soaked in urine (i.e., a watery composition), is to        prevent adherence of foreign bodies to it. Therefore, any        composition targeted to adhere to the internal wall of the        bladder will have to overcome the difficulty of adhering to such        mucosal membrane. Furthermore, since the mucosal layer is in        constant contact with urine, in order to coat it, a hypothetical        option would be to initially dry it. However, such an operation        is not acceptable in present medical practice. Another        complication stems from the membrane structure, which is        composed from several cell layers where the outermost is the        terminally differentiated ‘umbrella’ cells that are the        urothelium most superficial layer. Regular biological adhesives,        such that are used to stop bleeding (e.g. Tabotamp that is        distributed by Johnson & Johnson, NJ, USA), can bond strongly        through the wet surface and peel-off that delicate, outermost        layer and thus damage the membrane. The achievement of a        satisfactory non-damaging coating of wet, non-adherent mucosal        tissue is very challenging indeed.    -   The bladder's natural expansion and collapse. The bladder is        essentially muscular tissue and its wall is naturally highly        flexible. The inner volume of a mature bladder varies greatly,        from a collapsed or ‘empty’ state with a volume of 0-30 ml up to        a filled bladder with a volume of up to 500-600 ml (though the        bladder usually fills only up to 150-200 ml before micturition        point, that is, when the individual feels the urge to urinate        and indeed vacates the bladder. Therefore, providing a        composition that has the capacity to adhere and conform to the        bladder wall without damaging the outer layer, adapt itself to        the bladder's morphology in spite of the great variance in        volume and the fact that it is permanently changing its form and        volume and stay adhered to it is considered an enormous        challenge.    -   Further to the above-mentioned difficulties to adhere onto a        mucosal membrane, it is also highly challenging to do so while        avoiding the peeling-off of the outermost layer of the        membrane—due to adhering shear forces or adhesion between tissue        areas. So while biological glues that can stop bleeding can also        adhere through the wet mucosal layer, their rigidity compromises        the integrity of the outermost layer and negates the required        therapeutic effect.    -   The same obstacles, to even greater extent, are relevant to the        treatment of the same cancer (transitional cell carcinoma) in        the upper urinary tract. TCC in the upper urinary tract is a        rare urological disease and has a propensity for multifocality,        local recurrence, and development of metastases. Almost 5% of        all urothelial neoplasms occur in the kidney and ureters. The        standard treatment for patients with upper tract TCC and a        normal kidney is a complete removal of the involved kidney,        ureter and bladder cuff. A less-invasive treatment, namely        resection of tumors followed by instillation with chemotherapy        or immunotherapy, is recommended for patients with anatomic or        functional solitary kidneys, bilateral upper-tract TCC, base        line renal insufficiency, or inability to tolerate major        surgery. Patients with a normal contralateral kidney who have        small, low-grade lesions can also be reasonable candidates for        this organ conserving management.    -   Topical immunotherapy or chemotherapy instillations for        treatment of UTUC are used as primary or adjuvant treatment in        order to reduce tumor recurrence. Topical instillation is        performed using either infusion through a percutaneous        nephrostomy tube, via a retrograde ureteral catheter, or by        retrograde reflux from the bladder with an indwelling double-J        stent. The main disadvantage in all these treatments is the        short residual duration of the active agent in the treated area        resulting in a low exposure time essential for treatment        efficacy. This may be one of the reasons for the shorter average        disease-free duration of upper tract TCC patients, compared to        lower tract TCC patients.    -   Another bladder disease is overactive bladder (OAB)—when the        bladder contracts suddenly without patient's control when the        bladder is not full. This syndrome affects an estimated 1 in 11        adults in the United States—especially common in older adults.    -   Current available treatment options for OAB are: bladder        training, pelvic floor exercises, drug therapy such as        anti-cholinergics, capsaicin, intravesical botulinum toxin        injections and in severe cases—bladder augmentation surgery.    -   Current oral drugs have high adverse event rate which leads to        patients' intolerability. Bladder instillation with        antimuscarines has been tried with lower adverse event rate, but        require recurrent catheterization due to the drug relatively        short half-life that reduces compliance.    -   Despite promising results the drawbacks to intravesical        botulinum toxin injections are numerous: the cystoscopic        injection requires proficiency and authorization of the        physician, some degree of anesthetic administration is required,        the botulinum toxin effects only the injected anatomical        locations and the treatment may lead to temporary urinary        retention and need for self-catheterization.        viii. Mechanical Support and Sustained Drug Release in        Minimally-Invasive Surgery

The limited number of access ports used in laparoscopic surgery mayimpair the ability of the surgeon to achieve adequate retraction andexposure, or to stabilize “moving targets” while operating on nonfixedorgans. Current solutions include adding more ports or using ahand-assisted technique—which have the disadvantages of being moreinvasive, possibly creating a cumbersome situation of multipleinstruments in a limited working space—or the use of temporary suturesthat pass through the abdominal wall.

The current invention provides means by which the organs can be heldmechanically in place by injecting the invented materials into thecavity and letting them to solidify and support the internal organs.This invented materials and method have the additional advantages of a)serving as a soothing dressing for the surgery cuts, b) contribution tohealing through sustained release of anti-infection drug and analgesicdrug for a therapeutically-significant duration (e.g., over 6 hours),and c) avoiding the need for further surgical or medical procedure, bynatural degradation of the material and its expelling from the body.

Similar method, but with a different family of materials can be used toprevent the adhesion of tissues between organs in the treated area,which may often occur during laparoscopic surgery.

ix. Current State-of-the-Art

To the best of the inventors' knowledge, a method for treating diseasesof the bladder or other inner cavities based on production of asolidified coating layer and affixing it onto the internal wall of thebladder or other cavities, followed by continuous release of thetherapeutic agent(s) from the coating, remains unknown in the art.

Furthermore, the application of the substrate material such that itcreates a continuous layer substantially affixed to the mucosal liningof the bladder or the outermost tissue of other internal cavity forprolonging the exposure of the drug to the targeted cells is neithertrivial nor obvious to any person skilled in the art.

Compositions known in the prior art as sustained-release substrates forthe treatment of bladder cancer (for example, the invention disclosed inU.S. Pat. Appl. US2006/0127420 to Chung) are lipophilic (oil-based).Given that the inner bladder wall is mucosal, essentially andpermanently soaked in an aqueous medium (i.e., urine), a drug embeddedin a hydrophilic medium would more effectively diffuse through thematrix/mixture and conveniently reach the bladder wall, allowing in thatway an intimate, continuous contact between the drug and the bladderwall.

Thus, there remains a long-felt and unmet need for a material with thefollowing properties: it is hydrophilic; it provides a homogeneous layerthat can securely adhere to the surfaces of internal body cavities, inparticular, mucosal tissue of such cavities as the bladder; it remainsattached despite the natural motions of the tissue to which it isattached; it is easily applied; it is biocompatible; it provides acontinuous sustained release of a therapeutic agent; the rate of releaseof the therapeutic agent is determined by the concentration of the agentand the rate of degradation of the material; and after the materialdegrades, it is excreted from the body by the body's own naturalprocesses.

SUMMARY OF THE INVENTION

The compositions disclosed herein, and the use thereof in treatments ofbladder disorders and urothelium dysfunction, are designed to meet thislong-felt need. In particular, mucoadhesive, bioerodible, biocompatiblethermoreversible hydrogel compositions comprising a therapeuticallyactive agent are disclosed that after insertion into a body cavity,solidify and form a drug reservoir inside the cavity. The compositionsand means for delivering them produce complete contact with and coverageof the bladder wall, thereby providing drug delivery to the entirebladder, in contrast to delivery induced by local injections. Theyadditionally produce a high topical drug concentration in the cavitywalls but low systemic exposure. By these means the invention hereindisclosed provides increased bioavailability, enhanced efficacy andreduced toxicity.

It comprises a series of systems that combine therapeutic materials andapplication means for the topical treatment of diseases that are focusedin internal cavities, such as a system for treating Superficial BladderCancer (SBC).

It is therefore an object of the present invention to disclose the useof a thermoreversible hydrogel composition in a system for delivery of atherapeutic agent to the urinary tract, characterized in that saidthermoreversible hydrogel composition comprises a thermoreversiblehydrogel. It is a further object of this invention to disclose such ause of a thermoreversible hydrogel composition in a system for deliveryof a therapeutic agent to the urinary tract, wherein said compositionadditionally comprises an effective amount of at least one therapeuticagent for treatment of the urinary tract.

It is a further object of the present invention to disclose the use of athermoreversible hydrogel composition in a system for delivery of atherapeutic agent to the urinary tract, characterized in that saidthermoreversible hydrogel composition comprises a thermoreversiblehydrogel characterized by: a viscosity of less than 200 Pa·s over atemperature range of 4° C.-12° C.; a viscosity of greater than 10³ Pa·sat 37° C.; a “peel strength” adhesiveness according to ASTM standardD2256-03 of 0.5-5.0 N cm⁻² at 37° C.; and, flexibility sufficient suchthat a 3 cm²×3 cm² section of bladder tissue layered with saidthermoreversible hydrogel at room temperature can be stretched to 9cm²×9 cm² without detachment of said thermoreversible hydrogel from saidbladder tissue.

It is a further object of this invention to disclose the use of ahydrogel composition in a system for delivery of a therapeutic agent tothe pleura, characterized in that said hydrogel composition comprises athermoreversible hydrogel characterized by a viscosity of less than 5Pa·s over a temperature range of 4° C.-12° C.; a viscosity of greaterthan 10³ Pa·s at 37° C.; a “peel strength” adhesiveness according toASTM standard D2256-03 of 0.5-5.0 N cm⁻² at 37° C.; and flexibilitysufficient such that a 3 cm²×3 cm² section of bladder tissue layeredwith said thermoreversible hydrogel at room temperature can be stretchedto 9 cm²×9 cm² without detachment of said thermoreversible hydrogel fromsaid bladder tissue.

It is a further object of this invention to disclose the use of ahydrogel composition in a system for delivery of a therapeutic agent tothe pleura, wherein said composition additionally comprises an effectiveamount of a therapeutic agent for treatment of the pleura.

It is a further object of this invention to disclose the use of athermoreversible hydrogel composition in a system for delivery of atherapeutic agent to a mucosal or serous membrane, characterized in thatsaid hydrogel composition comprises a thermoreversible hydrogelcharacterized by a viscosity of less than 5 Pa·s over a temperaturerange of 4° C.-12° C.; a viscosity of greater than 10³ Pa·s at 37° C.; a“peel strength” adhesiveness according to ASTM standard D2256-03 of0.5-5.0 N cm⁻² at 37° C.; and flexibility sufficient such that a 3 cm²×3cm² section of bladder tissue layered with said thermoreversiblehydrogel at room temperature can be stretched to 9 cm²×9 cm² withoutdetachment of said thermoreversible hydrogel from said bladder tissue.

It is a further object of this invention to disclose such a use of athermoreversible hydrogel composition in a system for delivery of atherapeutic agent to a mucosal or serous membrane, wherein saidcomposition additionally comprises an effective amount of a therapeuticagent for treatment of a mucosal or serous membrane.

It is a further object of this invention to disclose such a use of athermoreversible hydrogel composition in a system for delivery of atherapeutic agent to a mucosal or serous membrane, wherein said mucosalor serous membrane is located at an internal cavity chosen from thegroup consisting of, mouth, nasal sinus, paranasal sinus, gallbladder,esophagus, rectum, lungs, vagina, uterus, stomach, renal pelvis, pleura,abdomen, peritoneum, pelvis, liver, kidney, heart, intestine, brain, andvertebral column.

In some embodiments of the invention, said thermoreversible hydrogel isfurther characterized by a viscosity of less than 5 Pa·s over atemperature range of 4° C.-12° C. In some embodiments of the invention,the said thermoreversible hydrogel is further characterized by aviscosity of less than 0.5 Pa·s over a temperature range of 4° C.-12° C.In some embodiments of the invention, the thermoreversible hydrogel isfurther characterized by a viscosity of greater than 3×10³ at 37° C.

In some embodiments of the invention, said thermoreversible hydrogel hasa “peel strength” adhesiveness according to ASTM standard D2256-03 of1.0-5.0 N cm² at 37° C.

In some embodiments of the invention, said thermoreversible hydrogel isadditionally characterized by flexibility sufficient to permit thevolume of the tissue to which said composition is applied to expand by afactor of at least 3 without detachment of said gel from said tissue.

In some embodiments of the invention, said thermoreversible hydrogelcomprises between 20% and 30% (w/w) ethylene oxide/propylene oxide blockcopolymer; between 0.05% and 0.5% (w/w) hydroxypropylmethylcellulose(HPMC); between 0.1% and 2.5% (w/w) polyethylene glycol (PEG)-400; andthe balance water.

In some embodiments of the invention, said thermoreversible hydrogelcomprises between 20% and 30% (w/w) ethylene oxide/propylene oxide blockcopolymer; between 0.1% and 0.3% (w/w) HPMC; between 0.1% and 1.8% (w/w)PEG-400; and the balance water.

In some embodiments of the invention, said thermoreversible hydrogelcomprises between 18% and 40% (w/w) ethylene oxide/propylene oxide blockcopolymer; between 0.05% and 0.8% (w/w) CMC; between 0.1% and 2.5% (w/w)PEG-400; and the balance water.

In some embodiments of the invention, said thermoreversible hydrogelcomprises between 12-30% Pluronic F127; between 5-30% Pluronic F68;between 0.05% and 2% (w/w) CMC; between 0.1% and 2.5% (w/w) PEG-400; andthe balance water.

It is a further object of this invention to disclose such a use asdefined in any of the above, wherein said thermoreversible hydrogeladditionally comprises at least one component selected from the groupconsisting of adhesive and thickening compounds; bonding agents;pH-modifying substances; diffusion coatings; plasticizers; componentsfor increasing permeability within the formulation; swellableexcipients; matrix forming polymers; tight junction modifiers/cellmembrane permeability enhancers; and any combination thereof.

In some embodiments of the invention, said bonding agent is selectedfrom the group consisting of polycarbophil, cellulose, microcrystallinecellulose, cellulose derivatives, HPMC, hydroxypropylcellulose (HPC),low-substituted hydroxypropylcellulose, dicalcium phosphate, lactose,sucrose, ethylcellulose, hydroxypropymethylcellulose acetate succinate(HPMCAS), polyvinylpyrrolidone (PVP), vinylpyrrolidone/vinyl acetatecopolymer, polyethylene glycol, polyethylene oxide, polymethacrylates,polyvinyl alcohols (PVA), partially hydrolysed polyvinyl acetate (PVAc),polysaccharides, hyaluronic acid, fats, fatty acid derivatives, and anycombination thereof. In some embodiments of the invention, saiddiffusion coating is chosen from the group consisting of ethylcellulosesand polymethacrylates, cellulose acetate and cellulose acetate butyrateor any combination thereof.

In some embodiments of the invention, said component for increasingpermeability within the formulation is chosen from the group consistingof polyethylene glycols, PVP, PVA, HPMC, HPC, hydroxyethylcelluloses(HEC), methylcellulose (MC), carboxymethylcelluloses and their salts,dextrins, maltodextrins, cylcodextrins, dextrans, urea, salts, sugars,sugar alcohols, and any combination thereof.

In some embodiments of the invention, said swellable excipient isselected from the group consisting of polyvinylpyrrolidones,crospovidones, crosslinked sodium carboxymethylcellulose, crosslinkedsodium carboxymethylstarch, polyethylene oxides, polymethyacrylates,L-HPC, cellulose acetate, ethylcellulose, polymethacrylates,high-molecular weight polyethylene oxides, xanthan gum, copolymers ofvinylpyrrolidone and vinyl acetate, polyvinylpyrrolidones,crospovidones, crosslinked sodium carboxymethylcellulose, crosslinkedsodium carboxymethylstarch, poly(hydroxyalkyl methacrylate), alginates,galactomannans, and any combination thereof.

In some embodiments of the invention, said matrix forming polymer isselected from the group consisting of hydroxyethylmethylcelluloses, HPC,HEC, MC, ethylcelluloses, alkylcelluloses, hydroxyalkylcelluloses,hydroxyalkylmethylcelluloses, sodium CMCs, alginates, galactomannans,xanthans, polyethylene oxides, polyacrylic acids, polymethacrylic acids,polymethacrylic acid derivatives, polyvinyl alcohols, partiallyhydrolysed polyvinyl acetate, polyvinylpyrrolidone, agar, pectin, gumarabic, tragacanth, gelatin, starch, starch derivatives poly(propyleneoxide) (PPO), poly(lactide-co-glycolic acid) (PLGA),poly(N-isopropylacrylamide) (PNIPAM), poly(propylene fumarate) (PPF),polyurethane (PU), poly(organophosphazene) (POP), stearic acid,poly(acrylic acid), glyceryl stearate, cetearyl alcohol, sodium stearoyllactylate, hydroxy-lanolin, and any combination thereof.

In some embodiments of the invention, said tight junction modifier/cellmembrane permeability enhancer is chosen from the group consisting ofanionic surfactants, non-anionic surfactants, charged polymers, dimethylsulfoxide (DMSO), decylmethyl sulfoxide, tert-butyl cyclohexanol, fattyacids their esters and salts, ethanol, nicotinamide, urea,perfluoropolyether, monoterpene ketones, disodium citrate, succinic acidand tris.

In some embodiments of the invention, said surfactant is chosen from thegroup consisting of polysorbates, sodium dodecyl sulfate, and dextransulfate.

In some embodiments of the invention, said charged polymer is chosenfrom the group consisting of chitosan poly-arginine, polylysine, andaliginate.

In some embodiments of the invention, said monoterpene ketone is chosenfrom the group consisting of like (−) menthol, (−) menthone, peppermintoil, and spearmint oil.

In some embodiments of the invention, said thermoreversible hydrogel isadditionally used as a biological glue.

It is a further object of this invention to disclose such a use asdefined in any of the above, further characterized in that saidcomposition releases said therapeutic agent, over a temperature range of36° C.-42° C. and a pH range of between 5.5 and 8.0, at a rate of 80% ina time range of between 3 and 30 hours.

It is a further object of this invention to disclose such a use asdefined in any of the above, further characterized in that saidcomposition releases said therapeutic agent, over a temperature range of36° C.-42° C. and a pH range of between 1 and 9.0, at a rate of 80% in atime range of between 3 and 30 hours.

It is a further object of this invention to disclose such a use asdefined in any of the above, further characterized in that saidcomposition releases said therapeutic agent, over a temperature range of36° C.-42° C. and a pH range of between 1 and 9.0, at a rate of 80% in atime range of between 2 and 4 weeks.

It is a further object of this invention to disclose such a use asdefined in any of the above, wherein said therapeutic agent fortreatment of the urinary tract is selected from the group consisting ofantineoplastic agents, chemotherapeutic agents, anti-infective agents,antimicrobial agents, antiparasitic agents, antiviral agents, agentsacting on the blood, antihemorrhagics, antithrombotic agents,antifungals, antiseptics, agents for treating diseases of thegenito-urinary system, anti-inflammatory agents, neurological agents,gene therapy agents, corticosteroids, analgesic and anesthetic agents,growth factors, VEGF, inhibitory factors, LIF, proteins, mucin, and anycombination thereof.

It is a further object of this invention to disclose such a use asdefined in any of the above, wherein said therapeutic agent fortreatment of the urinary tract is selected from the group consisting ofMitomycin C, Deoxrubicin, Valrubicin, and Gemcitabine, Thiotepa,Ethoglucid (Epodyl), Epirubicin, Pirarubicin, Apaziquone, Vicinium,botulinium toxin, and interleukin-2.

It is a further object of this invention to disclose such a use asdefined in any of the above, wherein said system further comprises asecond hydrogel composition used subsequently, said second hydrogelcomposition comprising a thermoreversible hydrogel characterized by aviscosity of less than 200 Pa·s over a temperature range of 4° C.-12°C.; a viscosity of greater than 10³ Pa·s at 37° C.; a “peel strength”adhesiveness according to ASTM standard D2256-03 of 0.5-5.0 N cm⁻² at37° C.; and flexibility sufficient such that a 3 cm²×3 cm² section ofbladder tissue layered with said thermoreversible hydrogel at roomtemperature can be stretched to 9 cm²×9 cm² without detachment of saidthermoreversible hydrogel from said bladder tissue; and an effectiveamount of a cell cycle modifying agent for synchronization of cell cyclechosen from the group consisting of chalones, colcemid, methotrexate,and thymidine.

It is a further object of this invention to disclose a use as defined inany of the above, wherein said pharmaceutically active agent isbotulinum toxin. In some embodiments of the invention, saidpharmaceutically active agent is selected from the group consisting ofotulinum toxin A, botulinum toxin B, botulinum toxin C₁, botulinum toxinD, botulinum toxin E, botulinum toxin F and botulinum toxin G. In someembodiments of the invention, said pharmaceutically active agent isselected from the group consisting of anticholinergic agents, andantimuscarinic agents, beta-3 agonists, pentosan polysulfate,amitriptyline, heparin-binding epidermal growth factor (HB-EGF),all-trans-retinoic acid (ATRA), derivatives of antiproliferative factor(APF), cannabinoid-2 receptor blockers, memantine, N-methyl-D-aspartate(NMDA)-receptor blockers, Parthenolide, inhibitors of NF-κB, calciumglycerophosphate, Metamucil, and Chondroitin sulfate.

It is a further object of this invention to disclose a use as defined inany of the above, wherein said composition is for treatment of a bladderdisorder characterized by bladder spasms. In some embodiments of theinvention, said disorder is selected from the group consisting ofurinary incontinence due to unstable bladder or unstable detrusorsphincter; voiding complications due to detrusor overactivity or ahypertrophied bladder neck; neurogenic bladder dysfunction secondary toconditions such as Parkinson's disease, spinal cord injury, stroke ormultiple sclerosis; and bladder pathologies characterized by a spasmreflex, overactive bladder, interstitial cystitis, stress incontinence,urge incontinence, or neurogenic bladder.

It is a further object of this invention to disclose a use as defined inany of the above, wherein said composition comprises 0.2-20 U/kg bodyweight of botulinum toxin.

It is a further object of this invention to disclose a use as defined inany of the above, wherein said biocompatible mucoadhesivethermoreversible hydrogel is characterized by an instillationtemperature of between 20° C. and 42° C.

It is a further object of this invention to disclose a use as defined inany of the above, wherein said biocompatible mucoadhesivethermoreversible hydrogel is characterized by an instillationtemperature of between 4° C. and 60° C.

It is a further object of this invention to disclose a use as defined inany of the above, wherein said biocompatible mucoadhesivethermoreversible hydrogel is characterized by a gel point below 33° C.

It is a further object of this invention to disclose such a use asdefined in any of the above, wherein said system is furthercharacterized in that it is designed to release said therapeutic agentcontinuously for at least 12 hours.

It is a further object of this invention to disclose a method foradministering a therapeutic agent to the internal surface of an internalbody cavity, comprising:

-   -   incorporating an effective amount of said therapeutic agent into        a biocompatible sustained-release material chosen from the group        consisting of (a) biocompatible sustained-release materials        comprising between 20% and 30% (w/w) ethylene oxide/propylene        oxide block copolymer, between 0.05% and 0.5% (w/w) HPMC,        between 0.1% and 2.5% (w/w) PEG-400, and the balance water;        and (b) biocompatible sustained-release materials comprising        between 20% and 30% (w/w) ethylene oxide/propylene oxide block        copolymer; between 0.1% and 0.3% (w/w) HPMC; between 0.1% and        1.8% (w/w) PEG-400; and the balance water;    -   inflating a balloon to open said internal body cavity to a        substantially symmetrical shape;    -   introducing said biocompatible sustained-release material into        said internal body cavity;    -   applying said biocompatible sustained-release material to at        least part of the internal surface of said internal body cavity;    -   applying force to said material, thereby spreading it over at        least part of the internal surface of said internal cavity;    -   causing said biocompatible sustained-release material to adhere        to said internal surface of said internal body cavity; and,    -   releasing said therapeutic agent into said internal body cavity        under conditions chosen from the group consisting of:        -   a temperature of 36-42° C.; pH in the range of 5.5-8.0, and            at a rate of 80% in a time range of 3 to 30 hours;        -   a temperature of 36-42° C.; pH in the range of 1-9.0, and at            a rate of 80% in a time range of 3 to 30 hours; and,        -   a temperature of 36-42° C.; pH in the range of 1-9.0, and at            a rate of 80% in a time range of 2 to 4 weeks.

It is a further object of this invention to disclose such a method,additionally comprising a step of providing said material with at leastone component selected from the group consisting of adhesive andthickening compounds; at least one substance selected from the groupconsisting of polycarbophil, cellulose, microcrystalline cellulose,cellulose derivatives, dicalcium phosphate, lactose, PVP and sucrose,ethylcellulose, hydroxypropymethylcellulose acetate succinate (HPMCAS),PVP, vinylpyrrolidone/vinyl acetate copolymer, polyethylene glycol,polyethylene oxide, polymethacrylates, polyvinyl alcohols (PVA),partially hydrolysed polyvinyl acetate (PVAc), polysaccharides, fats andfatty acid derivatives and any combination thereof, pH-modifyingsubstances; at least one substance selected from the group consisting ofethylcelluloses and polymethacrylates, cellulose acetate, celluloseacetate butyrate and any combination thereof, plasticizers; at least onesubstance selected from the group consisting of polyvinylpyrrolidones,crospovidones, crosslinked sodium carboxymethylcellulose, crosslinkedsodium carboxymethylstarch, polyethylene oxides, polymethyacrylates,low-substituted hydroxypropylmethylcellulose (L-HPC), cellulose acetate,ethylcellulose and polymethacrylates, high-molecular weight polyethyleneoxides, xanthan gum, copolymers of vinylpyrrolidone and vinyl acetate,polyvinylpyrrolidones, crospovidones, crosslinked sodiumcarboxymethylcellulose, crosslinked sodium carboxymethylstarch,poly(hydroxyalkyl methacrylate), alginates, galactomannans, and anycombination thereof; at least one substance chosen from the groupconsisting of polyethylene glycols, PVP, PVA, HPC,hydroxyethylcelluloses (HEC), MC, carboxymethylcelluloses or theirsalts, dextrins, maltodextrins, cylcodextrins, dextrans urea, salts,sodium chloride, potassium chloride, ammonium chloride, sugars, sucrose,lactose, glucose, fructose, maltose, sugar alcohols, mannitol, sorbitol,xylitol, lactitol, and any combination thereof, at least one substancechosen from the group consisting of hydroxyethylmethylcelluloses,hydroxypropylcelluloses (HPC), hydroxyethylcelluloses methylcelluloses(MC), ethylcelluloses, alkylcelluloses, hydroxy-alkylcelluloseshydroxyalkylmethylcelluloses, sodium carboxymethylcelluloses (NaCMC),alginates, galactomannans, xanthans, polyethylene oxides, polyacrylicacids, polymethacrylic acids, polymethacrylic acid derivatives,polyvinyl alcohols (PVA), partially hydrolysed polyvinyl acetate (PVAc),polyvinylpyrrolidone (PVP), agar, pectin, gum arabic, tragacanth,gelatin, starch, starch derivatives and any combination thereof; and anycombination thereof.

It is a further object of this invention to disclose such a method,wherein said step of releasing said therapeutic material into saidinternal body cavity further comprises a step of dissolving saidbiocompatible sustained-release material in body fluid found within saidinternal body cavity, whereby said therapeutic agent is released fromsaid biocompatible sustained-release material.

It is a further object of this invention to disclose such a method,wherein said step of applying force to said material further comprises astep of filling said catheter balloon with a liquid and positioning thepatient to utilize the gravitational forces directly toward the targettissue during the solidification of the material and cause optimaladhesion to that target tissue.

It is a further object of this invention to disclose such a method,wherein said step of applying force to said material further comprises astep of changing the position of the patient before applying partialdoses of material to enable substantially full coating of the wholetargeted internal cavity surface.

It is a further object of this invention to disclose such a method,wherein said step of applying force to said material further comprisesinserting a magnetic material chosen from the group consisting of amagnet, a magnetic metal, and a ferromagnetic liquid into said balloon;and applying an external magnetic field such that the interaction saidmagnetic material and said external magnetic field causes said magneticmaterial to move within said balloon, thereby applying force to at leastpart of the internal surface of said internal cavity.

It is therefore an object of the present invention to disclose ahydrophilic biocompatible sustained-release material comprising PluronicF-127 and Hydroxypropylmethylcellulose (HPMC) in amounts effective toproduce a hydrogel composition of sufficiently low viscosity at roomtemperature to be injectable into an internal body cavity via a tubeinserted within a urinary catheter, trocar or the working channel of anendoscope.

It is a further object of this invention to disclose such a material,further comprising PEG-400 or PEG-800.

It is a further object of this invention to disclose such a material asdefined in any of the above, additionally comprising at least one activeingredient (API).

It is a further object of this invention to disclose such a material asdefined in any of the above, wherein said API comprises excipientsselected from acids or buffer substances adapted to modify the pH so asto reduce the dependence of said release of active ingredient on the pHof the release medium.

It is a further object of this invention to disclose such a material asdefined in any of the above, additionally comprising at least one morecompounds selected from adhesive and thickening compounds; bondingagents; pH-modifying substances; diffusion coating; plasticizers; matrixpermeability increasing components; swellable excipients matrix-formingpolymers; diffusion-controlled or pulsatile formulations; reversethermal gelaton agents or any combination thereof.

It is a further object of this invention to disclose such a material asdefined in any of the above, wherein said adhesive and thickeningcompounds are selected from a group consisting of polycarbophil, acrylicacid crosslinked, divinyl glycol, hydroxypropylmethylcellulose (HPMC),polyvinylpyrrolidone (PVP), methylcellulose (MC),hydroxy-propylcellulose (HPC), other hydroxyalkylcelluloses,hydroxyalkylmethylcelluloses, carboxy-methylcelluloses and saltsthereof, polyacrylic acids, polymethacrylates, gelatin, starch or starchderivatives, as well as gums like guar gum and xanthan gum or anycombination thereof.

It is a further object of this invention to disclose such a material asdefined in any of the above, wherein said bonding agents are selectedfrom a group consisting of polycarbophil, cellulose, microcrystallinecellulose, cellulose derivatives such as, for example, HMPC, HPC andlow-substituted hydroxypropylcellulose (L-HPC), dicalcium phosphate,lactose, PVP and sucrose, ethylcellulose, hydroxypropymethylcelluloseacetate succinate (HPMCAS), PVP, vinylpyrrolidone/vinyl acetatecopolymer, polyethylene glycol, polyethylene oxide, polymethacrylates,polyvinyl alcohols (PVA), partially hydrolysed polyvinyl acetate (PVAc),polysaccharides (e.g. alginic acid, alginates, galactomannans) waxes,fats and fatty acid derivatives or any combination thereof.

It is a further object of this invention to disclose such a material asdefined in any of the above, wherein said pH-modifying substances areselected from a group consisting of acids, bases and buffer, adipicacid, malic acid, L-arginine, ascorbic acid, aspartic acid,benzenesulphonic acid, benzoic acid, succinic acid, citric acid,ethanesulphonic acid, 2-hydroxyethanesulphonic acid, fumaric acid,gluconic acid, glucuronic acid, glutamic acid, potassium hydrogentartrate, maleic acid, malonic acid, methanesulphonic acid,toluenesulphonic acid, trometamol, tartaric acid. Citric acid, succinicacid, tartaric acid, potassium hydrogen tartrate are preferably employedor any combination thereof.

It is a further object of this invention to disclose such a material asdefined in any of the above, wherein said diffusion coating are selectedfrom a group consisting of ethylcelluloses and polymethacrylates suchas, for example, EUDRAGIT® NE, EUDRAGIT® RS and RL, cellulose acetateand cellulose acetate butyrate or any combination thereof.

It is a further object of this invention to disclose such a material asdefined in any of the above, wherein the proportion of the plasticizeris from 0 to 50%, preferably 0 to 35% of the hydrogel composition.

It is a further object of this invention to disclose such a material asdefined in any of the above, wherein said water-soluble polymers areselected from a group consisting of polymerspolyethylene glycols, PVP,PVA, HPMC, HPC, hydroxyethylcelluloses (HEC), MC,carboxymethylcelluloses or their salts, dextrins, maltodextrins,cylcodextrins, dextrans urea, salts, sodium chloride, potassiumchloride, ammonium chloride, sugars, sucrose, lactose, glucose,fructose, maltose, sugar alcohols, mannitol, sorbitol, xylitol,lactitol, or any combination thereof.

It is a further object of this invention to disclose such a material asdefined in any of the above, wherein said swellable excipients areselected from a group consisting of polyvinylpyrrolidones,crospovidones, crosslinked sodium carboxymethylcellulose, crosslinkedsodium carboxymethylstarch, polyethylene oxides, polymethyacrylates,low-substituted hydroxypropylmethylcellulose (L-HPC), cellulose acetate,ethylcellulose and polymethacrylates, high-molecular weight polyethyleneoxides, xanthan gum, copolymers of vinylpyrrolidone and vinyl acetate,polyvinylpyrrolidones, crospovidones, crosslinked sodiumcarboxymethylcellulose, crosslinked sodium carboxymethylstarch,poly(hydroxyalkyl methacrylate), alginates and galactomannans andmixtures thereof or any combination thereof.

It is a further object of this invention to disclose such a material asdefined in any of the above, wherein said reverse thermal gelatoncompositions are selected from a group consisting of Poloxamers,Poloxamer 407 or any combination thereof.

It is a further object of this invention to disclose such a material asdefined in any of the above, wherein said water-swellable matrix-formingpolymers compositions are selected from a group consistingohydroxy-propylmethylcelluloses (HPMC), hydroxyethylmethylcelluloses,hydroxypropylcelluloses (HPC), hydroxyethylcelluloses methylcelluloses(MC), ethylcelluloses, alkylcelluloses, hydroxy-alkylcelluloseshydroxyalkylmethylcelluloses, sodium carboxymethylcelluloses (NaCMC),alginates, galactomannans such as, for example, guar and carob flour,xanthans, polyethylene oxides, polyacrylic acids, polymethacrylic acids,polymethacrylic acid derivatives, polyvinyl alcohols (PVA), partiallyhydrolysed polyvinyl acetate (PVAc), polyvinylpyrrolidone (PVP), agar,pectin, gum arabic, tragacanth, gelatin, starch or starch derivatives orany combination thereof.

It is a further object of this invention to disclose such a material asdefined in any of the above, wherein said material is formulated as ahomogeneous mixture.

It is a further object of this invention to disclose such a material asdefined in any of the above, wherein said material is administeredorally, topically, intranasal, vaginally, rectal, ocular and parenteralroutes.

It is a further object of this invention to disclose such a material asdefined in any of the above, further comprising lidocaine.

It is a further object of this invention to disclose such a material asdefined in any of the above, wherein said material is soluble in atleast one body fluid chosen from the group consisting of urine, serousfluids, and lymphatic fluids.

It is a further object of this invention to disclose such a material,wherein the solubility of said material is sufficiently high that saidmaterial will completely degrade in less than 4 weeks afterincorporation into an internal body cavity.

It is a further object of this invention to disclose such a material,wherein the solubility of said material is sufficiently high that saidmaterial will completely degrade in less than 24 hours afterincorporation into an internal body cavity.

It is a further object of this invention to disclose such a material,wherein the solubility of said material is sufficiently high that saidmaterial will completely degrade in less than 18 hours afterincorporation into an internal body cavity.

It is a further object of this invention to disclose such a material,wherein the solubility of said material is sufficiently high that saidmaterial will completely degrade in less than 16 hours afterincorporation into an internal body cavity.

It is a further object of this invention to disclose such a material asdefined in any of the above, wherein said material is adapted to exhibitreverse thermal gelling properties.

It is a further object of this invention to disclose such a material asdefined in any of the above, wherein said material is characterized by aviscosity of less than 200 Pa·s at a range of 8° C. to 25° C. andgreater than 3000 Pa·s at a range of 35° C.-37° C.

It is a further object of this invention to disclose such a material asdefined in any of the above, wherein said material is characterized by aviscosity of less than 200 Pa·s at 10° C. and greater than 3000 Pa·s at37° C. It is a further object of this invention to disclose such amaterial, wherein said material is characterized by a viscosity of lessthan 200 Pa·s at 10° C. and greater than 3500 Pa·s at 37° C.

It is a further object of this invention to disclose such a material asdefined in any of the above, wherein the instillation temperature ofsaid material is between 20° C. and 42° C.

It is a further object of this invention to disclose such a material,wherein said material is characterized by a gel point below 20° C.

It is a further object of this invention to disclose such a material asdefined in any of the above, adapted to adhere to the surface of mucosaltissue.

It is a further object of this invention to disclose such a material asdefined in any of the above, wherein said material is characterized by a“rolling ball” adhesiveness according to the ASTM D-3121-94 standard isless than 2 cm.

It is a further object of this invention to disclose such a material asdefined in any of the above, wherein said material is characterized by a“peel strength” adhesiveness according to the ASTM D-2256-03 standard isat least 1 N/cm².

It is a further object of this invention to disclose such a material asdefined in any of the above, wherein said material is characterized by awork of adhesion of at least 0.5 mJ.

It is a further object of this invention to disclose such a material,wherein said material is characterized by a work of adhesion of at least0.7 mJ.

It is a further object of this invention to disclose such a material,wherein said material is characterized by a work of adhesion of at least1 mJ.

It is a further object of this invention to disclose such a material asdefined in any of the above, wherein said material is characterized by apeak detachment force of at least 1.3 N.

It is a further object of this invention to disclose such a material,wherein said material is characterized by a peak detachment force of atleast 14.4 N.

It is a further object of this invention to disclose such a material,wherein said material is characterized by a peak detachment force of atleast 6.3 N.

It is a further object of this invention to disclose such a material,wherein said mucosal tissue comprises interior wall of at least oneselected from a group consisting of the urinary bladder, mouth, nasaland paranasal sinus, gallbladder, esophagus, rectum, lungs, vagina,uterus, stomach, renal pelvis, pleura, abdomen, peritoneum, pelvis,liver, kidney, heart, intestine, brain, vertebral column, or anycombination thereof.

It is a further object of this invention to disclose such a material,adapted to remain adherent to said mucosal tissue during the naturalexpansion on contraction of said urinary bladder or other organs.

It is a further object of this invention to disclose such a material asdefined in any of the above, further comprising an effective amount of atherapeutic agent.

It is a further object of this invention to disclose such a material,comprising 20-30% Pluronic F-127; 0-1.8% PEG-400; 0.1%-0.3% HPMC; aneffective amount of a therapeutic agent; and the balance water.

It is a further object of this invention to disclose such a material,comprising 20-30% Pluronic F-127; 0-2.5% PEG-400; 0.05%-0.5% HPMC; aneffective amount of a therapeutic agent; and the balance water.

It is a further object of this invention to disclose such a material,wherein said therapeutic agent is chosen from the group consisting ofMitomycin C, Deoxrubicin (with or without antibiotics), Valrubicin, andGemcitabine, Thiotepa, Ethoglucid (Epodyl), Epirubicin, Pirarubicin,Apaziquone, Botulinium Toxin and Vicinium.

It is a further object of this invention to disclose such a material,wherein said therapeutic agent is mitomycin C.

It is a further object of this invention to disclose such a material,wherein said mitomycin C is present in a concentration of 0.05%-0.2%.

It is a further object of this invention to disclose such a material,wherein said mitomycin C is present in a concentration of 0.025%-0.3%.

It is a further object of this invention to disclose such a material asdefined in any of the above, wherein the solubility of said material issufficiently low that said therapeutic agent is continuously releasedfor at least 12 hours.

It is a further object of this invention to disclose such a material asdefined in any of the above, wherein the solubility of said material issufficiently low that said therapeutic agent is continuously releasedfor at least 2 hours.

It is a further object of this invention to disclose such a material asdefined in any of the above, wherein the solubility of said material issufficiently low that said therapeutic agent is continuously releasedfor at least 16 hours.

It is a further object of this invention to disclose such a material asdefined in any of the above, wherein the solubility of said material issufficiently low that said therapeutic agent is continuously releasedfor at least 18 hours.

It is a further object of this invention to disclose the use of thematerial as defined in any of the above in a sustained-release topicaltreatment of a condition affecting an internal body cavity.

It is a further object of this invention to disclose the use of thematerial as defined in any of the above in a sustained-release topicaltreatment for at least one selected from a group of internal cavitiesthat includes, among others, the urinary bladder, mouth, nasal andparanasal sinus, gallbladder, esophagus, rectum, lungs, vagina, uterus,stomach, renal pelvis, pleura, abdomen, peritoneum, pelvis, liver,kidney, heart, intestine, brain, vertebral column, etc.

It is a further object of this invention to disclose a material asdefined in any of the above, additionally comprising at least one activeingredient (API).

It is a further object of this invention to disclose a material, whereinsaid therapeutic agent is Botulinium Toxin, that intended for treating abladder disorder wherein said bladder disorder is characterized bybladder spasms.

In some embodiments, said disorder is selected from the group consistingof urinary incontinence due to unstable bladder or unstable detrusorsphincter; voiding complications due to detrusor overactivity or ahypertrophied bladder neck; neurogenic bladder dysfunction secondary toconditions such as Parkinson's disease, spinal cord injury, stroke ormultiple sclerosis; and bladder pathologies characterized by a spasmreflex, overactive bladder, interstitial cystitis, stress incontinence,urge incontinence, or neurogenic bladder.

In some embodiments, said step of applying to a bladder cavity abiocompatible mucoadhesive thermoreversible hydrogel into which apharmaceutically active agent for treating said bladder disorder hasbeen incorporated comprises applying to a bladder cavity a biocompatiblemucoadhesive thermoreversible hydrogel comprising 0.2-20 U/kg bodyweight of botulinum toxin.

It is a further object of this invention to disclose such a material asdefined in any of the above, wherein said material comprises excipientsselected from acids or buffer substances adapted to modify the pH so asto reduce the dependence of said release of active ingredient on the pHof the release medium.

It is a further object of this invention to disclose such a material asdefined in any of the above, additionally comprising at least one morecompounds selected from adhesive and thickening compounds; bondingagents; pH-modifying substances; diffusion coating; plasticizers; matrixpermeability increasing components; swellable excipients matrix-formingpolymers; diffusion-controlled or pulsatile formulations; reversethermal gelaton agents or any combination thereof.

It is a further object of this invention to disclose such a material asdefined in any of the above, wherein said adhesive and thickeningcompounds are selected from a group consisting of polycarbophil, acrylicacid crosslinked, divinyl glycol, hydroxypropylmethylcellulose (HPMC),polyvinylpyrrolidone (PVP), methylcellulose (MC),hydroxy-propylcellulose (HPC), other hydroxyalkylcelluloses,hydroxyalkylmethylcelluloses, carboxy-methylcelluloses and saltsthereof, polyacrylic acids, polymethacrylates, gelatin, starch or starchderivatives, as well as gums like guar gum and xanthan gum or anycombination thereof.

It is a further object of this invention to disclose such a material asdefined in any of the above, wherein said bonding agents are selectedfrom a group consisting of polycarbophil, cellulose, microcrystallinecellulose, cellulose derivatives such as, for example, HMPC, HPC andlow-substituted hydroxypropylcellulose (L-HPC), dicalcium phosphate,lactose, PVP and sucrose, ethylcellulose, hydroxypropymethylcelluloseacetate succinate (HPMCAS), PVP, vinylpyrrolidone/vinyl acetatecopolymer, polyethylene glycol, polyethylene oxide, polymethacrylates,polyvinyl alcohols (PVA), partially hydrolysed polyvinyl acetate (PVAc),polysaccharides (e.g. alginic acid, alginates, galactomannans) waxes,fats and fatty acid derivatives or any combination thereof.

It is a further object of this invention to disclose such a material asdefined in any of the above, wherein said pH-modifying substances areselected from a group consisting of acids, bases and buffer, adipicacid, malic acid, L-arginine, ascorbic acid, aspartic acid,benzenesulphonic acid, benzoic acid, succinic acid, citric acid,ethanesulphonic acid, 2-hydroxyethanesulphonic acid, fumaric acid,gluconic acid, glucuronic acid, glutamic acid, potassium hydrogentartrate, maleic acid, malonic acid, methanesulphonic acid,toluenesulphonic acid, trometamol, tartaric acid. Citric acid, succinicacid, tartaric acid, potassium hydrogen tartrate are preferably employedor any combination thereof.

It is a further object of this invention to disclose such a material asdefined in any of the above, wherein said diffusion coating are selectedfrom a group consisting of ethylcelluloses and polymethacrylates suchas, for example, EUDRAGIT® NE, EUDRAGIT® RS and RL, cellulose acetateand cellulose acetate butyrate or any combination thereof.

It is a further object of this invention to disclose such a material asdefined in any of the above, wherein said plasticizers are selected froma group consisting of citric acid derivatives, triethyl citrate,tributyl citrate, acetyl triethyl citrate, phthalic acid derivatives,dimethyl phthalate, diethyl phthalate, dibutyl phthalate, benzoic acidand benzoic esters, other aromatic carboxylic esters, trimellithicesters, aliphatic dicarboxylic esters, dialkyl adipates, sebacic esters,in particular diethyl sebacate, tartaric esters, glycerol monoacetate,glycerol diacetate or glycerol triacetate, polyols, glycerol,1,2-propanediol, polyethylene glycol of varying chain length, fattyacids and derivatives, glycerol monostearates, acetylated fatty acidglycerides, castor oil and other natural oils, Miglyol, fatty acidalcohols, cetyl alcohol, cetylstearyl alcohol or any combinationthereof.

It is a further object of this invention to disclose such a material asdefined in any of the above, wherein the proportion of the plasticizeris from 0 to 50%, preferably 0 to 35% of the hydrogel composition.

It is a further object of this invention to disclose such a material asdefined in any of the above, wherein said water-soluble polymers areselected from a group consisting of polymerspolyethylene glycols, PVP,PVA, HPMC, HPC, hydroxyethylcelluloses (HEC), MC,carboxymethylcelluloses or their salts, dextrins, maltodextrins,cylcodextrins, dextrans urea, salts, sodium chloride, potassiumchloride, ammonium chloride, sugars, sucrose, lactose, glucose,fructose, maltose, sugar alcohols, mannitol, sorbitol, xylitol,lactitol, or any combination thereof.

It is a further object of this invention to disclose such a material asdefined in any of the above, wherein said swellable excipients areselected from a group consisting of polyvinylpyrrolidones,crospovidones, crosslinked sodium carboxymethylcellulose, crosslinkedsodium carboxymethylstarch, polyethylene oxides, polymethyacrylates,low-substituted hydroxypropylmethylcellulose (L-HPC), cellulose acetate,ethylcellulose and polymethacrylates, high-molecular weight polyethyleneoxides, xanthan gum, copolymers of vinylpyrrolidone and vinyl acetate,polyvinylpyrrolidones, crospovidones, crosslinked sodiumcarboxymethylcellulose, crosslinked sodium carboxymethylstarch”poly(hydroxyalkyl methacrylate), alginates and galactomannans andmixtures thereof or any combination thereof.

It is a further object of this invention to disclose such a material asdefined in any of the above, wherein said reverse thermal gelatoncompositions are selected from a group consisting of Poloxamers,Poloxamer 407 or any combination thereof.

It is a further object of this invention to disclose such a material asdefined in any of the above, wherein said water-swellable matrix-formingpolymers compositions are selected from a group consistingohydroxy-propylmethylcelluloses (HPMC), hydroxyethylmethylcelluloses,hydroxypropylcelluloses (HPC), hydroxyethylcelluloses methylcelluloses(MC), ethylcelluloses, alkylcelluloses, hydroxy-alkylcelluloseshydroxyalkylmethylcelluloses, sodium carboxymethylcelluloses (NaCMC),alginates, galactomannans such as, for example, guar and carob flour,xanthans, polyethylene oxides, polyacrylic acids, polymethacrylic acids,polymethacrylic acid derivatives, polyvinyl alcohols (PVA), partiallyhydrolysed polyvinyl acetate (PVAc), polyvinylpyrrolidone (PVP), agar,pectin, gum arabic, tragacanth, gelatin, starch or starch derivatives orany combination thereof.

It is a further object of this invention to disclose such a material asdefined in any of the above, wherein said material is administeredorally, topically, intranasal, vaginally, rectal, ocular and parenteralroutes.

It is a further object of this invention to disclose such a material asdefined in any of the above, wherein said API is released at temperatureof 36-42° C.; pH in the range of 5.5-8.0, at a rate of 80% in a timerange of 3 to 30 hours.

It is a further object of this invention to disclose such a material asdefined in any of the above, wherein said API is released at temperatureof 36-42° C.; pH in the range of 1-8.0, at a rate of 80% in a time rangeof 2 hours to 4 weeks.

It is a further object of this invention to disclose such a material asdefined in any of the above, wherein said API is dissolved, suspendedand/or solid, amorphous or crystalline form.

It is a further object of this invention to disclose such a material asdefined in any of the above, wherein said API is provided in variousparticle sizes, in unground, ground or in micronized form.

It is a further object of this invention to disclose such a material asdefined in any of the above, wherein said material is administeredtopically; further wherein said API is selected from a group consistingof Antineoplastic drugs; Chemotherapeutic agents; Anti-infective agents,Antimicrobial drugs, Antiparasitic agents, Antivirals, Antihemorrhagics,Antithrombotic agents, antianemic drugs, Dermatologic drugs,antifungals, antiseptic, Genito-urinary system drugs, Gastrointestinalsystem, antiobesity, acid related disorders, Metabolism drugs,Anti-inflammatory product, Musculoskeletal system acting drugs,Respiratory drugs, Otological drugs, Anti-infective drugs,Corticosteroids drugs, Analgesics drugs, GeneTherapy, Antiparasiticsdrugs, Growth factors, VEGF, Inhibitory factors, LIF or any combinationthereof.

It is a further object of this invention to disclose such a material asdefined in any of the above, wherein said material further comprising atleast one selected from a group consisting of Poly (propyleneoxide)—PPO, Poly (lactide-co-glycolic acid)—PLGA, Poly(N-isopropylacrylamide)—PNIPAM, Poly (propylene fumerate)—PPF, Poly(urethane)—PU, Poly (organophosphazene)—POP, Poloxamers of the typePEO-PPO-PEO (Poly (ethylene oxide), Poly (propylene oxide), Poly(ethylene oxide)) such as poloxamer 68, 88, 98, 108, 124, 127,188, 237,338 and 407, Stearic Acid, Poly (acrilic acid), Glyceryl Stearate,Cetearyl Alcohol, Sodium Stearoyl Lactylate, Hydroxy-Lenolin or anycombination thereof.

It is a further object of this invention to disclose such a material,wherein said material is used as biological glue.

It is a further object of this invention to disclose a method foradministering a therapeutic agent to the internal surface of an internalbody cavity, comprising:

-   -   incorporating an effective amount of said therapeutic agent into        a biocompatible sustained-release material;    -   inflating a balloon to open said internal body cavity to a        substantially symmetrical shape;    -   introducing said biocompatible sustained-release material into        said internal body cavity;    -   applying said biocompatible sustained-release material to at        least part of the internal surface of said internal body cavity;    -   applying force to said material, thereby spreading it over at        least part of the internal surface of said internal cavity;    -   causing said biocompatible sustained-release material to adhere        to said internal surface of said internal body cavity; and,    -   releasing said therapeutic agent into said internal body cavity.

It is a further object of this invention to disclose such a method asdefined in any of the above, additionally comprising step of providingsaid material with at least one active ingredient (API).

It is a further object of this invention to disclose such a method asdefined in any of the above, wherein said material comprises excipientsselected from acids or buffer substances adapted to modify the pH so asto reduce the dependence of said release of active ingredient on the pHof the release medium.

It is a further object of this invention to disclose such a method asdefined in any of the above, additionally comprising step of providingsaid material with at least one more compounds selected from adhesiveand thickening compounds; bonding agents; pH-modifying substances;diffusion coating; plasticizers; matrix permeability increasingcomponents; swellable excipients matrix-forming polymers;diffusion-controlled or pulsatile formulations; reverse thermal gelatonagents or any combination thereof.

It is a further object of this invention to disclose such a method asdefined in any of the above, wherein said adhesive and thickeningcompounds are selected from a group consisting of polycarbophil, acrylicacid crosslinked, divinyl glycol, hydroxypropylmethylcellulose (HPMC),polyvinylpyrrolidone (PVP), methylcellulose (MC),hydroxy-propylcellulose (HPC), other hydroxyalkylcelluloses,hydroxyalkylmethylcelluloses, carboxy-methylcelluloses and saltsthereof, polyacrylic acids, polymethacrylates, gelatin, starch or starchderivatives, as well as gums like guar gum and xanthan gum or anycombination thereof.

It is a further object of this invention to disclose such a method asdefined in any of the above, wherein said bonding agents are selectedfrom a group consisting of polycarbophil, cellulose, microcrystallinecellulose, cellulose derivatives such as, for example, HMPC, HPC andlow-substituted hydroxypropylcellulose (L-HPC), dicalcium phosphate,lactose, PVP and sucrose, ethylcellulose, hydroxypropymethylcelluloseacetate succinate (HPMCAS), PVP, vinylpyrrolidone/vinyl acetatecopolymer, polyethylene glycol, polyethylene oxide, polymethacrylates,polyvinyl alcohols (PVA), partially hydrolysed polyvinyl acetate (PVAc),polysaccharides (e.g. alginic acid, alginates, galactomannans) waxes,fats and fatty acid derivatives or any combination thereof.

It is a further object of this invention to disclose such a method asdefined in any of the above, wherein said pH-modifying substances areselected from a group consisting of acids, bases and buffer, adipicacid, malic acid, L-arginine, ascorbic acid, aspartic acid,benzenesulphonic acid, benzoic acid, succinic acid, citric acid,ethanesulphonic acid, 2-hydroxyethanesulphonic acid, fumaric acid,gluconic acid, glucuronic acid, glutamic acid, potassium hydrogentartrate, maleic acid, malonic acid, methanesulphonic acid,toluenesulphonic acid, trometamol, tartaric acid. Citric acid, succinicacid, tartaric acid, potassium hydrogen tartrate are preferably employedor any combination thereof.

It is a further object of this invention to disclose such a method asdefined in any of the above, wherein said diffusion coating are selectedfrom a group consisting of ethylcelluloses and polymethacrylates suchas, for example, EUDRAGIT® NE, EUDRAGIT® RS and RL, cellulose acetateand cellulose acetate butyrate or any combination thereof.

It is a further object of this invention to disclose such a method asdefined in any of the above, wherein said plasticizers are selected froma group consisting of citric acid derivatives, triethyl citrate,tributyl citrate, acetyl triethyl citrate, phthalic acid derivatives,dimethyl phthalate, diethyl phthalate, dibutyl phthalate, benzoic acidand benzoic esters, other aromatic carboxylic esters, trimellithicesters, aliphatic dicarboxylic esters, dialkyl adipates, sebacic esters,in particular diethyl sebacate, tartaric esters, glycerol monoacetate,glycerol diacetate or glycerol triacetate, polyols, glycerol,1,2-propanediol, polyethylene glycol of varying chain length, fattyacids and derivatives, glycerol monostearates, acetylated fatty acidglycerides, castor oil and other natural oils, Miglyol, fatty acidalcohols, cetyl alcohol, cetylstearyl alcohol or any combinationthereof.

It is a further object of this invention to disclose such a method asdefined in any of the above, wherein the proportion of the plasticizeris from 0 to 50%, preferably 0 to 35% of the hydrogel composition.

It is a further object of this invention to disclose such a method asdefined in any of the above, wherein said water-soluble polymers areselected from a group consisting of polymerspolyethylene glycols, PVP,PVA, HPMC, HPC, hydroxyethylcelluloses (HEC), MC,carboxymethylcelluloses or their salts, dextrins, maltodextrins,cylcodextrins, dextrans urea, salts, sodium chloride, potassiumchloride, ammonium chloride, sugars, sucrose, lactose, glucose,fructose, maltose, sugar alcohols, mannitol, sorbitol, xylitol,lactitol, or any combination thereof.

It is a further object of this invention to disclose such a method asdefined in any of the above, wherein said swellable excipients areselected from a group consisting of polyvinylpyrrolidones,crospovidones, crosslinked sodium carboxymethylcellulose, crosslinkedsodium carboxymethylstarch, polyethylene oxides, polymethyacrylates,low-substituted hydroxypropylmethylcellulose (L-HPC), cellulose acetate,ethylcellulose and polymethacrylates, high-molecular weight polyethyleneoxides, xanthan gum, copolymers of vinylpyrrolidone and vinyl acetate,polyvinylpyrrolidones, crospovidones, crosslinked sodiumcarboxymethylcellulose, crosslinked sodium carboxymethylstarch”poly(hydroxyalkyl methacrylate), alginates and galactomannans andmixtures thereof or any combination thereof.

It is a further object of this invention to disclose such a method asdefined in any of the above, wherein said reverse thermal gelatoncompositions are selected from a group consisting of Poloxamers, inparticular Poloxamer 407 or any combination thereof.

It is a further object of this invention to disclose such a method asdefined in any of the above, wherein said water-swellable matrix-formingpolymers compositions are selected from a group consistingohydroxy-propylmethylcelluloses (HPMC), hydroxyethylmethylcelluloses,hydroxypropylcelluloses (HPC), hydroxyethylcelluloses methylcelluloses(MC), ethylcelluloses, alkylcelluloses, hydroxy-alkylcelluloseshydroxyalkylmethylcelluloses, sodium carboxymethylcelluloses (NaCMC),alginates, galactomannans such as, for example, guar and carob flour,xanthans, polyethylene oxides, polyacrylic acids, polymethacrylic acids,polymethacrylic acid derivatives, polyvinyl alcohols (PVA), partiallyhydrolysed polyvinyl acetate (PVAc), polyvinylpyrrolidone (PVP), agar,pectin, gum arabic, tragacanth, gelatin, starch or starch derivatives orany combination thereof.

It is a further object of this invention to disclose such a method asdefined in any of the above, additionally comprising step ofadministering said material orally, topically, intranasal, vaginally,rectal, ocular and parenteral routes or any combination thereof.

It is a further object of this invention to disclose such a method asdefined in any of the above, wherein said API is released at temperatureof 36-42° C.; pH in the range of 5.5-8.0, at a rate of 80% in a timerange of 3 to 30 hours.

It is a further object of this invention to disclose such a method asdefined in any of the above, wherein said API is released at temperatureof 36-42° C.; pH in the range of 1-8.0, at a rate of 80% in a time rangeof 2 to 4 weeks.

It is a further object of this invention to disclose such a method asdefined in any of the above, wherein said API is released at temperatureof 36-42° C.; pH in the range of 1-9.0, at a rate of 80% in a time rangeof 3 to 30 hours.

It is a further object of this invention to disclose such a method asdefined in any of the above, wherein said API is dissolved, suspendedand/or solid, amorphous or crystalline form.

It is a further object of this invention to disclose such a method asdefined in any of the above, wherein said API is provided in variousparticle sizes, in unground, ground or in micronized form.

It is a further object of this invention to disclose such a method asdefined in any of the above, wherein said material is administeredtopically; further wherein said API is selected from a group consistingof Antineoplastic drugs; Chemotherapeutic agents; Anti-infective agents,Antimicrobial drugs, Antiparasitic agents, Antivirals; Drugs acting onthe blood and blood forming organs, Antihemorrhagics, Antithromboticagents, antianemic drugs, Dermatologic drugs, antifungals, antiseptic,Genito-urinary system drugs, Gastrointestinal system, antiobesity, acidrelated disorders, Metabolism drugs, Anti-inflammatory product,Musculoskeletal system acting drugs; Neurological drugs, Respiratorydrugs, Cardio-vascular drugs, Otological drugs, Anti-infective drugs,Corticosteroids drugs, Analgesics and anesthetics drugs, GeneTherapy,Antiparasitics drugs, Growth factors, VEGF, Inhibitory factors, LIF orany combination thereof.

It is a further object of this invention to disclose such a method asdefined in any of the above, additionally comprising step of providingsaid material with at least one selected from a group consisting of Poly(propylene oxide)—PPO, Poly (lactide-co-glycolic acid)—PLGA, Poly(N-isopropylacrylamide)—PNIPAM, Poly (propylene fumerate)—PPF, Poly(urethane)—PU, Poly (organophosphazene)—POP, Poloxamers of the typePEO-PPO-PEO (Poly (ethylene oxide), Poly (propylene oxide), Poly(ethylene oxide)) such as poloxamer 68, 88, 98, 108, 124, 127,188, 237,338 and 407, Stearic Acid, Poly (acrilic acid), Glyceryl Stearate,Cetearyl Alcohol, Sodium Stearoyl Lactylate, Hydroxy-Lenolin or anycombination thereof.

It is a further object of this invention to disclose such a method,wherein said biocompatible sustained-release material is thebiocompatible sustained-release material as defined in any of the above.

It is a further object of this invention to disclose such a method asdefined in any of the above, wherein said internal body cavity is atleast one selected from a group of internal cavities that includes,among others, the urinary bladder, mouth, nasal and paranasal sinus,gallbladder, esophagus, rectum, lungs, vagina, uterus, stomach, renalpelvis, pleura, abdomen, peritoneum, pelvis, liver, kidney, heart,intestine, brain, vertebral column, etc.

It is a further object of this invention to disclose such a method asdefined in any of the above, wherein said therapeutic agent is atherapeutic agent for treatment of superficial bladder cancer.

It is a further object of this invention to disclose such a method asdefined in any of the above, wherein said step of introducing saidbiocompatible sustained-release material into said internal body cavityfurther comprises a step of introducing said biocompatiblesustained-release material into said internal body cavity via acatheter.

It is a further object of this invention to disclose such a method asdefined in any of the above, wherein said step of releasing saidtherapeutic material into said internal body cavity further comprises astep of dissolving said biocompatible sustained-release material in bodyfluid within said internal body cavity, whereby said therapeutic agentis released from said biocompatible sustained-release material.

It is a further object of this invention to disclose such a method asdefined in any of the above, wherein said step of applying force to saidmaterial further comprises a step of filling said catheter balloon withwater and positioning the patient to utilize the gravitational forcesdirectly toward the target tissue during the solidification of thematerial and cause optimal adhesion to that target tissue.

It is a further object of this invention to disclose such a method asdefined in any of the above, wherein said step of applying gravitationalforce to said material further comprises a step of changing the positionof the patient before applying partial doses of material to enablesubstantially full coating of the whole targeted internal cavitysurface.

It is a further object of this invention to disclose such a method asdefined in any of the above, wherein said step of applying force to saidmaterial further comprises a step of filling said balloon with a liquiddenser than water.

It is a further object of this invention to disclose such a method,wherein said liquid denser than water comprises a solution of salt inwater, said solution having a density greater than 1.0 g/cm³.

It is a further object of this invention to disclose such a method,wherein said liquid denser than water comprises a solution of glucose inwater, said solution having a density greater than 1.0 g/cm³.

It is a further object of this invention to disclose such a method asdefined in any of the above, wherein said step of applying force to saidmaterial further comprises steps of

-   -   inserting a first magnetic means into said balloon; and,    -   applying a second magnetic means such that the magnetic        attraction of said first magnetic means and said second magnetic        means causes said first magnet to move within said balloon,        whereby said attraction applies force to at least part of the        internal surface of said internal cavity.

It is a further object of this invention to disclose such a method asdefined in any of the above, wherein said step of applying force to saidmaterial further comprises steps of

-   -   introducing a ferromagnetic liquid into said balloon; and,    -   applying magnetic means such that the magnetic attraction of        said magnetic means and ferromagnetic particles suspended within        said ferromagnetic liquid causes said ferromagnetic particles to        move within said balloon, thereby applying force to at least        part of the internal surface of said internal cavity.

It is a further object of this invention to disclose such a method asdefined in any of the above, wherein said step of applying force to saidmaterial further comprises steps of

-   -   introducing into said balloon a substance chosen from (a) a        constant or electric magnet, (b) a piece of ferromagnetic        material, and (c) a ferromagnetic liquid;    -   placing the patient within an MRI apparatus; and,    -   activating said MRI apparatus such that the magnetic field of        said MRI apparatus causes said substance to move within said        balloon, thereby applying force to at least part of said        internal cavity.

It is a further object of this invention to disclose such a method asdefined in any of the above, wherein the solubility of said material issufficiently high that said material will completely degrade in lessthan 4 weeks after incorporation into an internal body cavity.

It is a further object of this invention to disclose such a method asdefined in any of the above, wherein said material is characterized by aviscosity of less than 200 Pa·s at a range of 10° C. to 25° C. andgreater than 3000 Pa·s at a range of 35° C.-37° C.

It is a further object of this invention to disclose such a method asdefined in any of the above, wherein said material is characterized by aviscosity of less than 200 Pa·s at 10° C. and greater than 3000 Pa·s at37° C.

It is a further object of this invention to disclose such a method asdefined in any of the above, wherein the instillation temperature ofsaid material is between 4° C. and 60° C.

It is a further object of this invention to disclose such a method asdefined in any of the above, wherein said material comprising 20-30%Pluronic F-127; 0-1.8% PEG-400; 0.1%-0.3% HPMC; an effective amount of atherapeutic agent; and the balance water.

It is a further object of this invention to disclose such a method asdefined in any of the above, wherein said material comprising 20-30%Pluronic F-127; 0-2.5% PEG-400; 0.05%-0.5% HPMC; an effective amount ofa therapeutic agent; and the balance water.

It is a further object of this invention to disclose such a method asdefined in any of the above, additionally comprising step of providingsaid material as biological glue.

It is a further object of this invention to disclose such a method asdefined in any of the above, wherein the weight of the balloon filledwith a liquid denser than water is used for the application of the gel(utilizing its gravity).

BRIEF DESCRIPTION OF THE FIGURES

The invention disclosed herein is described with reference to thefigures, in which:

FIG. 1 presents a flow diagram of the creation of a hydrogel compositionin a drug delivery system for treatment of internal cavities;

FIGS. 2A-2B present graphs showing the amplitude (FIG. 2A) andinter-contraction interval (FIG. 2B) of bladder contractions in acontrol group of rats following treatment with saline or one of fourthermoreversible hydrogel formulations;

FIGS. 3A-3D present graphs illustrating the MMC cytotoxicity whendifferent MMC concentrations are used in saline and in DTC-2respectively;

FIGS. 4A-4B present graphically the results of a study of the effect ofbotulinum toxin gel on contraction (FIG. 4A) and inter-contractioninterval (FIG. 4B) of animal bladder as model for overactive bladdercontraction;

FIGS. 5A-5B present graphs representing results of measurements ofrheological parameters of the material according to several embodimentsof the invention herein disclosed;

FIG. 6 presents a graph showing the delivery of MMC to pig bladdertissue by use of a gel according to one embodiment of the presentinvention;

FIG. 7 presents results of measurements of in vitro release of Lidocainehydrochloride (10 and 20 mg/ml) from reverse thermal hydrogel (including27% Ethylene Oxide/Propylene Oxide Block Copolymer, 1% PEG-400, 0.2%Hydroxypropylmethyl cellulose in water) and Cephalexin (1 mg/ml) fromreverse thermal hydrogel (20.0% Pluronic F-127, 10% Pluronic F68 (10.0%)1.0% PEG-400 0.4% CMC sodium in water; and,

FIG. 8 shows results for the dissolution rate of hydrogels according toseveral different embodiments of the invention.

FIG. 9 presents a schematic illustration of the muscular paresis gradingscale.

FIGS. 10A-10B present graphs showing the contraction amplitude (FIG.10A) and inter-contraction intervals (FIG. 10B) of bladder hyperactivity(chronic bladder cystitis) induced by intraperitoneal injection ofcyclophosphamide in rats, showing suppression of bladder hyperactivityby treatment with botulinum toxin, and the improved suppression ofbladder hyperactivity when the botulinum toxin is administered within athermoreversible hydrogel according to several non-limiting embodimentsof the invention disclosed herein.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In the following description, various aspects of the invention will bedescribed. For the purposes of explanation, specific details are setforth in order to provide a thorough understanding of the invention. Itwill be apparent to one skilled in the art that there are otherembodiments of the invention that differ in details without affectingthe essential nature thereof. Therefore the invention is not limited bythat which is illustrated in the figure and described in thespecification, but only as indicated in the accompanying claims, withthe proper scope determined only by the broadest interpretation of saidclaims.

As used herein, the term “internal cavity” is used to describe parts inthe body that are either accessible through an orifice—e.g., mouth,bladder, intestine, esophagus, rectum, lungs, vagina, stomach, renalpelvis, etc.—or by way of minimally invasive, surgery—e.g., pleura,abdomen, peritoneum, pelvis, etc. The definition includes artificiallymade or enlarged cavities in adipose tissues and fibrous capsules ininternal organs such as the kidney, heart, intestine, etc. that areaccessible by image guided laparoscopic techniques.

As used herein, the term “DTC” is used to refer generically to thematerials disclosed in the present invention. The terms “DTCx” and“DTC-n” (where n is an integer) are used to refer to particularembodiments, either generically (DTCx) or specifically (e.g. DTC-2).

The present invention provides a bioerodible, biocompatible gel mixedwith an active agent, such as chemotherapy agent like MMC orgemcitabine, or immunotherapy such as BCG (bacillus Calmette-Guerin),which is inserted into the upper urinary tract via a designatedcatheter, solidifies and forms a drug reservoir at the destinedtreatment area such as the renal pelvis. The diffusion of the drug fromthe gel and the erosion of the gel by the urine or the biodegradabilityof the gel, deliver drug to the tissue—producing prolonged high topicaldrug concentration but low systemic exposure. This, the system increasesbioavailability, reduces toxicity and improves treatment efficacy.Furthermore, loading the material with significant concentration ofchemotherapy agent and applying the material directly over a tumor for aprolonged duration, may ablate non-resected tumors that are in closecontact with the material.

The present invention provides a design of such gel compositions that isbased on the characteristics of the internal cavities to be treated andthe specific requirements for said treatments in order to determine therequired properties of hydrogel systems that can satisfy all theserequirements. A flow diagram for creation of hydrogel composition isillustrated in FIG. 1 . This structured set of gel properties enablesthe formulation of gel systems for optimal drug delivery. The presentinvention provides a structured design and test flow that assuresoptimal hydrogels for optimal treatments.

In some embodiments, the present invention additionally provides abioerodible, biocompatible hydrogel that that is mixed with aneurological drug such as botulinum toxin, is inserted into the bladder,solidifies and forms a drug reservoir inside the bladder. The erosion ofthe material in the urine, promotes topical drug delivery and increasesthe drug affinity to the bladder wall tissue producing high topical drugconcentration in the bladder wall and at the same time keeps a lowsystemic exposure. The system provides drug delivery to the entirebladder resulting in total tissue contact with the deliveredneurological drug as opposed to delivery induced by local injections.

The invented material includes a mixture of hydrogel with botuliniumtoxin (A, B, C1, D, E, F and G and equivalent neurological drugs) forthe treatment of disorders characterized by bladder spasms (eg. urgeincontinence due to unstable bladder or unstable detrusor, sphincter orneurogenic bladder, etc.). The hydrogel mixed with botulinium toxin willbe instilled into the bladder without injections into the bladder tissueand its effect will be.

The present invention also includes the use of the novel pharmaceuticalformulation or admix for producing medicaments which are intended forthe treatment and/or prevention of disorders in humans. These systemscontain drugs embedded in a slowly degrading biocompatible admix and arecombined with administering means, so that the materials can beintroduced in a minimally invasive manner into a body cavity and providea prolonged exposure of the cavity tissue to the drug, thus improvingthe treatment efficacy in terms of improved therapeutic effect of thedrug and reduced tissue damage. The admix/mixture is biocompatible anddissolves in body fluids such as urine, serous fluids or lymphaticfluids, and then it is expelled from the body.

The aim of the prolonged exposure of target tissue to drugs releasedfrom the coating is to enhance the efficacy of the drug in topicaltreatment of that target tissue, while reducing potential systemicadverse effects to other organs. As a specific example, the aim of theprolonged exposure of cancer cells to an anticancer drug released fromthe coating is to enhance the efficacy of the drug in killing cancercells and, therefore, potentially reduce the recurrence rate of cancertumors, while reducing the systemic effect of chemotherapy on otherparts of the patient body.

The homogeneous coating obtained in the invention disclosed herein,i.e., a solidified, unified and homogeneous layer that providescontinuous sustained release of therapeutic agents upon the innersurface of an internal body cavity, as herein disclosed, has to theinventors' knowledge never been produced or used clinically.

Thus, it is one object of the present invention to provide a materialthat includes active pharmaceutical ingredients (APIs) as a part of itsbasic formulation.

The current invention provides a platform for the redesign of drugs tomake them suitable for topical administration. Company studiesdemonstrated solubility and first order sustained release of MytomicinC, Doxorubicin and Gemcitabin (groups 1 & 2), Abamectin (group 3),exogenous glycosaminoglycan, group 4), Naproxen (group 5), lidocaine andvoltaren (group 6).

Among the drugs that can be administered topically are drugs that belongto the following families:

-   -   1. Antineoplastic drugs    -   2. Chemotherapeutic agents    -   3. Anti-infective agents (e.g. Antimicrobial drugs,        Antiparasitic agents, Antivirals)    -   4. Genito-urinary system drugs    -   5. Anti-inflammatory products    -   6. Analgesics    -   7. Musculoskeletal system acting drugs    -   8. Drugs acting on the blood and blood forming organs        (Antihemorrhagics, Antithrombotic agents, antianemic drugs)    -   9. Dermatologic drugs (antifungals, antiseptic)    -   10. Gastrointestinal system (antiobesity, acid related        disorders)    -   11. Metabolism drugs    -   12. Neurological drugs    -   13. Respiratory drugs including nasal drugs    -   14. Cardio-vascular drugs    -   15. Otological drugs    -   16. Anti-infective drugs    -   17. Corticosteroids drugs    -   18. Analgesics drugs    -   19. Antiparasitics drugs    -   20. Anasthetic Drugs

In other cases, the topical treatment is just evolving:

-   -   21. Growth factor (e.g., for treatment of heart muscle ischemia)    -   22. Gene Therapy agents    -   23. Mucin    -   24. Hyaluronic Acid

Drugs can be embedded as part of the invented materials as a singletherapeutic agent or as a combination. As an example, a mixturecontaining exogenous glycosaminoglycan and Naproxen can be combined in aspecific material for the treatment of interstitial cystitis foralleviating the inflammation symptoms and replacing the damaged mucosallining of the urinary bladder cavity that is typical for this disease.

The present invention provides a formulation/mixture which releaseactive ingredients (API) in a controlled fashion over a prolongedperiod. It is further an object of the present invention to providemedicament formulations with particular release profiles through whichthe prior art problems. As an example an average release rate between80% in 6 hours and 80% in 24 hours is maintained.

As standard, chemotherapy drugs are administered at a maximalconcentration level that is tolerable by patients. The present inventionstudy results demonstrate that a further improvement in efficacy can begained by increasing the exposure time to chemotherapy drugs. This is atthe core of the present invention.

In addition, the use of such formulation allows reduction of thefrequency of administration thus leads to improved patient's compliance.

A longer exposure time of the API has distinct advantages and it isexpected that a prolonged exposure with an API on use of a medicamentwith controlled release of active ingredient makes it possible toprolong substantially the time window in which improved therapy can beachieved. The use of the novel medicinal forms with controlled releaseof active ingredient is expected to achieve substantially more constantdrug levels and avoid the occurrence of level peaks, thus improving forexample the therapeutic efficacy and reducing the frequency andintensity of unwanted side effects.

In addition, the use of such admix/formulation/mixture allows thefrequency of administration to be reduced and thus leads to improvedacceptance and compliance by the patient.

It is expected as well that controlled-release of APIs prolong exposurewithout the occurrence of an increase in side effects, an adverse effecton reliability and safety of therapies. According to a preferredembodiment of the present invention the admix/formulation/mixturedescribed above, is for example in the form of activeingredient-containing hydrogels. These diffusion-controlled systems maybe completely diluted in the hydrogel admix/formulation/mixture or canbe multiparticulate, i.e. they may consist of a large number of coatedcores such as, for example, of microencapsulated APIs, where appropriatetogether with conventional excipients and carriers, as defined below forexample, is applied and subsequently coated with a diffusion coatingwhich may comprise plasticizers and other excipients. Thediffusion-controlled systems according to the invention may additionallyconsist of homogeneous active ingredient-containing cores which areproduced for example by granulation, rotor granulation, fluidized bedagglomeration, tableting, wet extrusion or melt extrusion, whereappropriate with spheronization, and are coated with a diffusion coatingwhich may comprise plasticizers and other excipients.

According to one embodiment, the present invention may provide acombination of APIs, one or more diluted or suspended in the gel and oneor more microencapsulated for slower release effect. For example, ananesthetic like lidocaine dissolved in the admix/formulation/mixture forimmediate anesthetic effect and encapsulated MMC for cancer treatmentthat is released after the bladder wall is insensitive and the patientcan stand the MMC therapy.

In a preferred embodiment of this invention, the activeingredient-containing particles comprise excipients such as, forexample, acids or buffer substances which modify the pH and thuscontribute to reducing the dependence of the release of activeingredient on the pH of the release medium.

According to a preferred embodiment of the present invention thematerial/formulation/mixture described above, additionally comprises atleast one ingredient selected from:

-   -   (a) adhesive and thickening compounds;    -   (b) bonding agents;    -   (c) pH-modifying substances;    -   (d) diffusion coating;    -   (e) plasticizers;    -   (f) Tight junction modifiers & permeability enhancers;    -   (g) matrix permeability increasing components;    -   (h) swellable excipients matrix-forming polymers;    -   (i) diffusion-controlled or pulsatile formulations; and,    -   (j) reverse thermal gelation agents.

The adhesive and thickening compounds preferably used in the productionof coated neutral pellets (e.g. consisting of sucrose, microcrystallinecellulose, citric acid) are polycarbophil (polymer of acrylic acidcrosslinked with divinyl glycol), hydroxypropylmethylcellulose (HPMC)and polyvinylpyrrolidone (PVP). It is likewise possible to employ othernaturally, synthetic or partially synthetic polymers such as, forexample methylcellulose (MC), hydroxy-propylcellulose (HPC), otherhydroxyalkylcelluloses and hydroxyalkylmethylcelluloses,carboxy-methylcelluloses and salts thereof, polyacrylic acids,polymethacrylates, gelatin, starch or starch derivatives, as well asgums like guar gum and xanthan gum.

The bonding agents employed for the production of activeingredient-containing microcapsules are for example polycarbophil,cellulose, microcrystalline cellulose, cellulose derivatives such as,for example, HMPC, HPC and low-substituted hydroxypropylcellulose(L-HPC), dicalcium phosphate, lactose, PVP and sucrose, ethylcellulose,hydroxypropymethylcellulose acetate succinate (HPMCAS), PVP,vinylpyrrolidone/vinyl acetate copolymer, polyethylene glycol,polyethylene oxide, polymethacrylates, polyvinyl alcohols (PVA),partially hydrolysed polyvinyl acetate (PVAc), polysaccharides (e.g.alginic acid, alginates, galactomannans) waxes, fats and fatty acidderivatives. The pH-modifying substances such as, for example, acids,bases and buffer substances are incorporated into the activeingredient-containing core. Addition of these substances makes itpossible to reduce markedly the pH-dependence of the release of theAPIs. Examples of suitable excipients which modify the pH in the activeingredient-containing cores are: adipic acid, malic acid, L-arginine,ascorbic acid, aspartic acid, benzenesulphonic acid, benzoic acid,succinic acid, citric acid, ethanesulphonic acid,2-hydroxyethanesulphonic acid, fumaric acid, gluconic acid, glucuronicacid, glutamic acid, potassium hydrogen tartrate, maleic acid, malonicacid, methanesulphonic acid, toluenesulphonic acid, trometamol, tartaricacid. Citric acid, succinic acid, tartaric acid, potassium hydrogentartrate are preferably employed. Particularly suitable for producingthe diffusion coating are ethylcelluloses and polymethacrylates such as,for example, EUDRAGIT® NE, EUDRAGIT® RS and RL. However, other materialssuch as, for example, cellulose acetate and cellulose acetate butyratecan also be employed as film-forming diffusion-controlling polymers.Examples of plasticizers used are citric acid derivatives (e.g. triethylcitrate, tributyl citrate, acetyl triethyl citrate), phthalic acidderivatives (e.g. dimethyl phthalate, diethyl phthalate, dibutylphthalate), benzoic acid and benzoic esters, other aromatic carboxylicesters (e.g. trimellithic esters), aliphatic dicarboxylic esters (e.g.dialkyl adipates, sebacic esters, in particular diethyl sebacate,tartaric esters), glycerol monoacetate, glycerol diacetate or glyceroltriacetate, polyols (e.g. glycerol, 1,2-propanediol, polyethylene glycolof varying chain length), fatty acids and derivatives (e.g. glycerolmonostearates, acetylated fatty acid glycerides, castor oil and othernatural oils, Miglyol) and fatty acid alcohols (e.g. cetyl alcohol,cetylstearyl alcohol).

The nature and amount of the plasticizer are chosen so that theabove-defined release according to the invention and the necessarystability of the medicinal forms is achieved. The proportion of theplasticizer is from 0 to 50%, preferably 0 to 35%, particularlypreferably 0 to 25% based on the mass of the hydrogel composition.

The release rate according to the invention is controlled by the gelcomposition. Certain components may increase the permeability of theadmix/formulation/mixture including water-soluble polymers such as, forexample, polyethylene glycols, PVP, PVA, HPMC, HPC,hydroxyethylcelluloses (HEC), MC, carboxymethylcelluloses or theirsalts, dextrins, maltodextrins, cylcodextrins, dextrans or other solublesubstances such as, for example, urea, salts (sodium chloride, potassiumchloride, ammonium chloride, etc.), sugars (sucrose, lactose, glucose,fructose, maltose etc.) and sugar alcohols (mannitol, sorbitol, xylitol,lactitol, etc.). Based on the mass of the hydrogel, the amount of thewater-soluble polymers ranges from 0 to 50%, preferably 0 to 35%,particularly preferably 0 to 20%, increasing permeability components maybe employed.

A further aspect of the present invention are coatedadmix/formulation/mixture which comprise one or more swellableexcipients which, on penetration of liquid through the membrane, swellgreatly and, through the swelling and volume expansion, cause thecoating to split. The splitting of the coating makes it possible for themedicinal substance to be released from the admix/formulation/mixture,usually in pulsatile form. Swellable excipients which these formulationsmay comprise are, for example, polyvinylpyrrolidones, crospovidones,crosslinked sodium carboxymethylcellulose, crosslinked sodiumcarboxymethylstarch, polyethylene oxides, polymethyacrylates,low-substituted hydroxypropylmethylcellulose (L-HPC). Examples ofsuitable coating materials are cellulose acetate, ethylcellulose andpolymethacrylates.

The described diffusion-controlled or pulsatile formulations can beemployed directly and unmodified as medicinal form. However, they mayalso be further processed, where appropriate with addition ofexcipients, to the final admix/formulation/mixture. In order to achievea desired release profile it is also possible to combine differentcoated formulations in one medicinal form, and administration of aninitial dose can take place for example by combination withrapid-release formulation particles, e.g. uncoated pellets, granules orpowder.

In a further embodiment of the admix/formulation/mixture containing thecontrolled release ingredient. These so-called admix/formulation/mixturerelease the active ingredient by diffusion and/or erosion.

The mass ratio of active ingredient to the total mass of theadmix/formulation/mixture in these novel formulations is in the rangefrom 1:1 to 1:10,000, preferably in the range from 1:2 to 1:1,000.

admix/formulation/mixture which can be employed are water-soluble,water-swellable or water-insoluble substances. The novel formulationspreferably comprise one or more water-swellable polymers.

A preferred family of candidates to be utilized as a basis for obtainingsaid hydrogel is group of tri-block copolymers designated as PEG-PPG-PEG(PEG=Polyethylene glycol and PPG=Polypropylene glycol) and calledPoloxamers, that produce reverse thermal gelaton compositions, i.e.,with the characteristic that their viscosity increases with increasingtemperature up to a point from which viscosity again decreases. Inparticular, Poloxamer 407 possesses a gelling temperature which is above10° C. but below the human body temperature, i.e., 37° C. Thischaracteristic may confer the ability of a composition containing thecompound to be injected or infused in liquid state into a bodily innercavity at a low temperature and, afterwards, as the composition warms,it solidifies into a gel, thus stabilizing upon the wall of the innerbody cavity.

This characteristic has allowed Poloxamer 407 (PF-127) to be used as acarrier for most routes of administration including oral, topical,intranasal, vaginal, rectal, ocular and parenteral routes.

Poloxamer 407 (PF-127) is a nonionic surfactant composed ofpolyoxyethylene-polyoxypropylene triblock copolymers in a concentrationranging from 20-30%. At low concentrations (10⁻⁴-10⁻⁵%) they formmonomolecular micelles, but higher concentrations result inmultimolecular aggregates consisting of a hydrophobic central core withtheir hydrophilic polyoxyethylene chains facing the external medium.Micellization occurs in dilute solutions of block copolymers in selectedsolvents above the critical micellar concentration, at a giventemperature. At higher concentrations, above a critical gelconcentration, the micelles can order into a lattice.

Aqueous solutions of poloxamers are stable in the presence of acids,alkalis, and metal ions. Commonly used poloxamers include the 88 (F-68grade), 237 (F-87 grade), 338 (F-108 grade) and 407 (F-127 grade) types,which are freely soluble in water. The “F” designation refers to theflake form of the product. PF-127 has a good solubilizing capacity, lowtoxicity and is, therefore, considered a good medium for drug deliverysystems.

PF-127 is a commercially available polyoxyethylene-polyoxypropylenetriblock copolymer that possesses a general formula E101 P56 E101, withan average molar mass of 13,000. It contains approximately 70% ethyleneoxide, which accounts for its hydrophilicity. It is one of the series ofpoloxamer ABA block copolymers. As said above, PF-127 aqueous solutionsof 20 to 30% w/w have the interesting characteristic of reverse thermalgelation, i.e., they are liquid at refrigerated temperatures (4-5° C.),but gel upon warming to room temperature. The gelation is reversibleupon cooling. This phenomenon, therefore, suggests that when poured ontothe skin or injected into a body cavity, the gel preparation will form asolid artificial barrier and a sustained release depot. Furthermore,PF-127 has been reported to be the least toxic of commercially availablecopolymers.

Water-soluble or water-swellable matrix-forming polymers preferablyemployed are hydroxy-propylmethylcelluloses (HPMC),hydroxyethylmethylcelluloses, hydroxypropylcelluloses (HPC),hydroxyethylcelluloses methylcelluloses (MC), ethylcelluloses, otheralkylcelluloses, hydroxy-alkylcelluloses andhydroxyalkylmethylcelluloses, sodium carboxymethylcelluloses (NaCMC),alginates, galactomannans such as, for example, guar and carob flour,xanthans, polyethylene oxides, polyacrylic acids, polymethacrylic acids,polymethacrylic acid derivatives, polyvinyl alcohols (PVA), partiallyhydrolysed polyvinyl acetate (PVAc), polyvinylpyrrolidone (PVP), agar,pectin, gum arabic, tragacanth, gelatin, starch or starch derivativesand mixtures of these substances.

In this connection, the admix/formulation/mixture according to theinvention should preferably comprise at least 0.1-2.0% of ahydroxypropylmethylcellulose type whose nominal viscosity (measured as2% strength aqueous solution at 20° C.) is at least 0.015 Pa s,preferably at least 0.050 Pa s. HPMC types preferably used have a degreeof substitution of methoxy groups of 16.5-30%, particularly preferably19-30%, and a degree of substitution of hydroxypropoxy groups of 4-32%,particularly preferably 4-12%.

In a particularly preferred embodiment of this invention, substanceswhich control the pH in the admix/formulation/mixture are incorporatedinto the admix/formulation/mixture. The addition of such pH-modifyingexcipients and/or the addition of substances which dissolve or aredissolved out of the admix/formulation/mixture as the pH increases, andthus increase the porosity or permeability of theadmix/formulation/mixture and/or promote erosion of theadmix/formulation/mixture, makes it possible to achieve a virtuallypH-independent release for these preferred embodiments of the presentinvention.

Examples of suitable excipients which can be added to theadmix/formulation/mixture according to the invention to achieve releasewhich is as far as possible pH-independent are the following substances:adipic acid, malic acid, L-arginine, ascorbic acid, aspartic acid,benzenesulfonic acid, benzoic acid, succinic acid, cellulose phthalates,in particular cellulose acetate phthalate andhydroxypropylmethylcellulose phthalate, cellulose succinates, inparticular cellulose acetate succinate and HPMCAS, citric acid,ethanesulfonic acid, 2-hydroxyethanesulphonic acid, fumaric acid,gluconic acid, glucuronic acid, glutamic acid, potassium hydrogentartrate, maleic acid, malonic acid, methanesulfonic acid,polymethacrylates (e.g. EUDRAGIT® types), toluenesulfonic acid,trometamol, tartaric acid. Citric acid, succinic acid, tartaric acid,HPMCAS, and polymethacrylates (e.g. EUDRAGIT® L) are preferablyemployed. If these excipients are present in theadmix/formulation/mixture according to the invention, they are typicallyadded in a proportion of from 10 to 50% based on the total mass of theadmix/formulation/mixture.

Examples of plasticizing excipients in the hydrogel formulation arepropylene glycol, glycerol, triethylene glycol, butanediols, pentanols,such as pentaerythritol, hexanols, long-chain alcohols, polyethyleneglycols, polypropylene glycols, polyethylene/propylene glycols,silicones, phthalic acid derivatives (e.g. dimethyl phthalate, diethylphthalate, dibutyl phthalate), benzoic acid and benzoic esters, otheraromatic carboxylic esters (e.g. trimellithic esters), citric acidderivatives (e.g. triethyl citrate, tributyl citrate, acetyl triethylcitrate), aliphatic dicarboxylic esters (e.g. dialkyl adipates, sebacicesters, in particular diethyl sebacate, tartaric esters), glycerolmonoacetate, glycerol diacetate or glycerol triacetate, fatty acids andderivatives (e.g. glycerol monostearates, acetylated fatty acidglycerides, castor oil and other natural oils, Miglyol), fatty acidalcohols (e.g. cetyl alcohol, cetylstearyl alcohol), sugars, sugaralcohols and sugar derivatives (e.g. erythritol, isomalt, lactitol,mannitol, maltitol, maltodextrin, xylitol). The concentration ofplasticizers is normally from 0 to 30%, preferably from 0 to 20% basedon the total mass of the gel.

Examples of further suitable water-swellable polymers which may beincorporated in the hydrogel are high-molecular weight polyethyleneoxides, xanthan gum, copolymers of vinylpyrrolidone and vinyl acetate,polyvinylpyrrolidones, crospovidones, crosslinked sodiumcarboxymethylcellulose, crosslinked sodium carboxymethylstarch,low-substituted hydroxypropylmethylcellulose (L-HPC), poly(hydroxyalkylmethacrylate), alginates and galactomannans and mixtures thereof.

The present invention further relates to the combination of formulationswith different release properties, e.g. rapid-release and slow-release,in one medicinal form.

As described above, according to one embodiment of the present inventiona admix/formulation/mixture which release active ingredients (API) in acontrolled fashion over a prolonged period is provided.

If necessary, the pH can be adjusted to 1-8.0 with a buffer composition.The release is carried out at a temperature of 36-42° C.

If necessary, the pH can be adjusted to 1-5.5 with a buffer composition.The release is carried out at a temperature of 36-42° C.

If necessary, the pH can be adjusted to 5.5-9.0 with a buffercomposition. The release is carried out at a temperature of 36-42° C.

The amount of active ingredient determined in this way is converted intopercent by mass of the amount of active ingredient employed.

The average release rate in the context of the present invention isdefined via the time until the release of active ingredient reaches 80%,whereas the initial release describes the percentage release of activeingredient after 30 minutes.

The admix/formulation/mixture according to the invention with controlledrelease of active ingredient preferably have an average release rate of80% in the time interval between 3 and 20 hours (80% in 3 hours and 80%in 20 hours).

The admix/formulation/mixture according to the invention with controlledrelease of active ingredient preferably have an average release rate of80% in the time interval between 2 and 4 weeks (80% in 2 hours and 80%in 4 weeks).

In a particularly preferred embodiment of the medicament formulationswith controlled release of active ingredient of the present invention,the formulation has an average release rate of 80% in the period from 3and 18 hours and an initial release not exceeding 65% of the activeingredient in the first 30 minutes of release.

The admix/formulation/mixture according to the present invention can beformulated so that a relative low initial release of 0 to 30% in thefirst 30 minutes or a relative high initial release of 30 to 60% of themedicinal substance in the first 30 minutes of medicinal substancerelease is achieved.

In a preferred embodiment of the admix/formulation/mixture of thepresent invention is characterized by an average release rate of 80% inthe period from 4 to 18 hours, this has a relatively low initial releaseof 0 to 25% in the first 30 minutes of release.

Another preferred configuration of the medicament formulations withcontrolled release of active ingredient has an average release rate of80% in the period from 3 to 16 hours and is distinguished by arelatively high initial release of 35 to 60% in the first 30 minutes ofrelease of active ingredient.

It should be emphasized that the admix/formulation/mixture withcontrolled release of active ingredient of this invention refers to allformulations in which the release of active ingredient is modified sothat it takes place with a slower delivery rate than from rapid-releasemedicinal forms such as, for example, a conventional instillationprocedure in the case of bladder cancer treatment.

Furthermore, the admix/formulation/mixture with controlled release ofactive ingredient of the present invention also include formulationswith delayed release in which the delivery of the active ingredient ismodified so that the release starts at a later time than with aconventional rapid-release medicinal form. The subsequent release from adelayed-release medicinal form may also take place in controlled fashionwith a reduced release rate.

The admix/formulation/mixture according to the invention with controlledrelease of active ingredient also include formulations with pulsatilerelease, where the delivery of active ingredient takes placeintermittently, and formulations in which different principles ofcontrolled delivery of active ingredient are combined.

The admix/formulation/mixture of this invention additionally includealso medicament formulations which comprise part of the activeingredient in rapid-release form and a further part of the activeingredient in controlled-release form.

The medicament formulations according to the invention may comprise theactive ingredient in dissolved, suspended and/or solid, amorphous orcrystalline form. The active ingredient can be employed in variousparticle sizes, e.g. in unground, ground or in micronized form, toproduce the admix/formulation/mixture according to the invention withcontrolled release of active ingredient.

According to one embodiment of the present invention provides a hydrogelcomposition that is intended to be used as a topical therapeutic agent,applied topically. Thus, it would be useful to have a device that allowsthe application of such said hydrogel composition once accessing a bodyorgan (inner cavity) through an orifice (either natural or artificial),so as to allow the coating of the inner wall of the organ with saidhydrogel gel. Such hydrogel composition will adhere well to said walland will (i) allow the controlled release of the drug or drugs; (b) willenable the gradual dilution of the hydrogel; and, (c) expelled from thebody in a reasonable period of time (e.g., 24 hrs).

According to another embodiment, cell line studies (see below) performedby the inventors of the present invention, demonstrate up to 30×highercell kill when cell lines are exposed to MMC for 10×longer time or to10×higher concentrations.

As standard, chemotherapy drugs are administered at a concentrationlevel that is tolerable by patients. The present invention study resultsdemonstrate that a further improvement in efficacy can be gained byincreasing the exposure time to chemotherapy drugs. This is at the coreof the present invention's concept.

Several of the present invention's materials incorporate a variety ofchemotherapy drugs for the treatment of bladder cancer—as non-limitedexamples, Mitomycin C, Deoxorubicin, Valrubicin and Gemcitabine are usedwith DTCx materials.

The present invention attempts to a) bring the largest part ofanticancer drug to contact with the tissue of the bladder wall and b)prolong the contact duration. These measures will probably improve thetreatment efficacy.

The present invention provides sustained release materials that areefficient for indications such as the non-limited example ofinterstitial cystitis. The DTC material is designed to stay in thebladder for a week and the medical drugs used are a combination ofHeparin and NSAID (Non-Steroidal Anti-Inflammatory Drug).

Prolonging the duration of tissue exposure to drug and significantlydelaying the expelling of the drug from the bladder result in a dramaticimprovement of the drug efficacy. The composition provided by thepresent invention, which furnishes a homogeneous, well-adhered coatingof the bladder inner wall, has the capability to provide such prolongeddrug release and overcome the difficulties of adherence to the internalwall of the bladder, such that the chemotherapy drug treatment durationis significantly prolonged and the cancer treatment efficacy isimproved.

This solidified, unified and homogeneous layer coating of the bladderwall possesses numerous advantages. Foremost is the ability tocontinuously release anticancer agents over a prolonged period of time,as opposed to the gold standard treatment of introducing a fixed amountof drug for a short and indeterminate period, which is expelled from thebladder when the patient first urinates after the instillationinduction.

A pre-clinical study of sows demonstrated a 20:1 higher level ofchemotherapy in the bladder, six hours after instillation with theinvented material compared to regular instillation of the same amount ofchemotherapy.

Interestingly, the developed polymeric materials allow their comfortableadministration through a thin tube, for example a urethral catheter,without exerting more than the common pressure required to inject asaline through such a device; and at the same time, as the liquidpolymer settles upon the bladder wall, it solidifies creating agelatinous film that then gradually releases the therapeutic ingredientupon said bladder wall.

This feature is of fundamental importance and is enabled by the factthat the polymeric composition was designed so as to possess reversethermal gelling properties (see below), that is, to possess lowviscosity at low temperatures (say, below 15° C.) and increasedramatically its viscosity as its temperature increases due to the bodyheat.

The coating layer created on the tissue of the internal cavity,disclosed in the present invention, is essentially a unified andhomogeneous layer of substrate applied and affixed to organ tissue.

Beyond maximization of the area of the tissue that is exposed to drug,this coating can also be used to control the distance between organs.Following are several examples:

-   -   Fixation and treatment of pleura. A common condition in several        lung and heart diseases is pleural effusion, when serous fluids,        pus or chyle accumulate into the space between the visceral        pleura and the parietal pleura layers surrounding the        lungs—condition called hydrothorax or pleural effusion.        Ordinarily there is little space between these layers, but        certain malignancies may cause the accumulation of fluids at        excessive levels that can impair breathing and cause severe        outcome. A standard treatment for larger effusions is the        insertion of intercostals drain, often accompanied by surgical        pleurodesis—in which the two pleural surfaces are scarred to        each other so that no fluid can accumulate between them—or even        open pleurectomy. This surgical joining of the layers is not        always successful, but when it does—it is permanent.    -   A material of the present invention can be administered into the        pleura cavity to adhere to the pleura layers and provide both a        mechanical bond and sustained release of drug for treatment of        the underlying malignancy (e.g. Tetracycline antibiotic for        bacterial infection, or NSAID such as Naproxen to treat fever        and inflammation. The pleura-hydrogel material is inserted into        the pleura space via a catheter or trocar, as non-viscous liquid        at a temperature that is below 15° C. and adheres to the        surrounding tissue as it heats to body temperature. The material        is designed to dissolve gradually into the pleura fluids over        less than a week and both maintain mechanical support and        release the drugs during that whole period. The main advantages        of this method are the combination of this procedure ability to        replace a more invasive one, the natural and easy application,        the reduction of tissue damage, the soothing effect of the        hydrogel and the enhanced healing effect of the sustained        release of anti-inflammatory agents.    -   Fixation of organs and prevention of tissue adhesion in the        abdomen during laparoscopy.    -   A material of the current invention can be introduced into the        abdomen cavity and provide mechanical support to the target        organs in the position that best fits the surgical procedure.        The peritoneum-hydrogel material can be inserted into the        peritoneum cavity via endoscope working channel, a catheter or        trocar, as non-viscous liquid at a temperature that is below        15° C. and adhere to the surrounding tissue as it heats to body        temperature. The material is designed to dissolve gradually into        the pleura fluids over less than a week and both maintain        mechanical support of the organs for several hours and release        the drugs during a longer period.    -   Similar method, but with different materials can be used to        prevent the adhesion of tissues between organs in the treated        area, which may often occur during laparoscopic surgery.    -   The main advantages of this method are the combination of its        ability to replace a more invasive procedure, the reduction of        tissue damage, the soothing effect of the hydrogel and the        enhanced healing effect of the sustained release of        anti-inflammatory agents. A further advantage is the prevention        of the need to remove the fixation surgically because of the        natural degradation and expelling of the invented material from        the treated area.

The release of drug from the admix/formulation/mixture occurs due to twophenomena that take place simultaneously after the gel is applied uponthe bladder wall: (1) Drug diffusion from the gel to the aqueous medium(urine); (2) Dissolution of the gel itself in the aqueous medium. We mayconsider two extreme cases in which the drug either diffuses very fastfrom the gel to the urine medium, or diffuses very slowly. In the firstcase, the gel will be depleted very fast of drug so the bladder wallcoated by the gel will “see” a low concentration of drug almost from thebeginning. On the other hand, the concentration of drug in the urinewill be higher and that is the concentration that uncoated parts of thebladder will see. If the case is the second (very slow release rate),the bladder wall coated by the gel will “see” a more or less highconcentration of drug for a long time, in fact, until the whole of thegel is dissolved in the urine phase. These two separate but intertwinedfactors, which we call “two clocks”, serve to design different therapiesutilizing different drugs and tailor-made polymeric carriers accordingto the medical needs.

A water-based admix/formulation/mixture is made of large molecules thatcreate spaces between the molecules that serve as matrix nodes. Thesespaces can be filled with drug molecules in a way that enables theirdiffusion into aqueous solution. The amount of drug molecules that canbe held in a admix/formulation/mixture depends on the three-dimensionalshape of the molecules as they are positioned in theadmix/formulation/mixture. The diffusion rate depends on themadmix/formulation/mixture three dimensional structure and packingfactor.

DTCx materials are designed according to the three dimensional shapes ofthe admix/formulation/mixture and the compound molecules.admix/formulation/mixture design that uses even, large molecules, maystore a high amount of drug, but will also enable fast diffusion out ofthe admix/formulation/mixture.

Admix/formulation/mixture design that combines larger and smallermolecules enables lower diffusion coefficients—leading to longer releasedurations—and, with some sacrifice of the included space volume.

Design of the admix/formulation/mixture that should store drugs forlonger times is based on a ‘matrix of polymer matrix’—i.e., higher orderpolymers. These structures can store drug molecules that start todiffuse only after the higher order structure is at least partiallydissolved. Poloxamer 407 (PF-127) is a nonionic surfactant composed ofpolyoxyethylene-polyoxypropylene copolymers. In general, poloxamers arecomposed of white, waxy, freeflowing granules that are practicallyodorless and tasteless. The “F” designation refers to the flake form ofthe product. PF-127 Is recognized as a pharmaceutical substance(Pharmacopeia/NF). It has a good solubilizing capacity, low toxicity andis therefore considered a good medium for drug delivery systems.

As described above, PF-127 is a commercially-availablepolyoxyethylene-polyoxypropylene triblock copolymer of general formulaE101 P56 E101, with an average molar mass of 13,000. It is one of theseries of poloxamer ABA block copolymers, whose members share thefollowing chemical formula:

PF-127 is more soluble in cold water than in hot water as a result ofincreased salvation and hydrogen bonding at lower temperatures. PF-127aqueous solutions of 20 to 30% w/w have the interesting characteristicof reverse thermal gelation, i.e., they are liquid at refrigeratedtemperatures (4-5° C.), but gel upon warming to room temperature. Thegelation is reversible upon cooling.

At low temperatures in aqueous solutions, a hydration layer surroundsPF-127 molecules. When the temperature is raised, the hydrophilic chainsof the copolymer become desolved as a result of the breakage of thehydrogen bonds that had been formed between the solvent and thesechains. This phenomenon favors hydrophobic interactions among thepolyoxypropylene domains and leads to gel formation. Because of thedehydration process, the hydroxyl groups become more accessible. Aliquid micellar phase is stable at low temperatures but transforms intothe cubic structure by increasing the temperature. At highertemperatures, a phase of hexagonal packed cylinders is formed.

Reverse thermal gelation and low toxicity have been the basis ofresearch into the use of PF-127 as a possible drug delivery system inhumans.

In a non-limiting example of DTCx materials in the context of thepresent invention, the hydrophilic character of the composition is anextremely important characteristic: It allows the polymer composition togradually dissolve in the urine after the drug has been essentiallyreleased and the therapeutic session has been concluded without leavingforeign polymer composition residues inside the bladder.

The present invention's DTCx materials use a combination of polymers anddrugs to obtain sustained release. Some of these materials have ReverseThermal Gelation (RTG) property, thus can be injected as a free-flowing,low-viscosity liquid at low temperatures and form a gel upon exposure tobody temperature. The DTCx materials present excellent rheologyproperties, high bio-adhesive capabilities in their gel state and hightherapeutic efficacy. The present invention's DTCx materials soften inwatery environment, such as exists in the bladder and will eventuallydissolve. If needed, cooling the material inside the bladder with coldsaline intravesical instillation will liquidize a DTCx material and washit out of the bladder.

Materials to be utilized in the present application require a number ofconditions to be fulfilled as follows:

-   -   i. Sustained release of API. The materials can be tailored to        release APIs for a pre-designed duration and according to a        pre-designed profile.    -   ii. Ability to insert material and coat through small orifices.        Introducing DTCx materials into internal cavities requires good        flow characteristics of the materials during insertion. One of        the ways to get that capability is by using materials that act        as ‘plasticizer’—helping the material flow without significantly        changing its viscosity and other rheology characteristics.    -   iii. Adhesion and solidifying to internal surfaces for        essentially pre-determined durations.

Some DTCx materials use polymers that have lower viscosities at lowtemperatures and gelate to high viscosities at body temperature. Thegelling from low viscosity to high viscosity occurs at a specifictemperature and produces mechanical tightening forces that enhanceadhesiveness of the material to the tissue.

The gelation temperature (gel point) is an important system parameter inthe design of the insertion, spreading and adhesiveness system. Theliquid DTCx material that enters the bladder has to be fixed and adheredto the bladder wall fast enough to prevent it from flowing undergravitational forces toward the lowest point in the bladder before it isfixated. In a non-limiting example, the specific formulation of the DTCxmay contain NaCl (table salt) that can lower the gelation temperatureand help in controlling the instillation process.

The determination of gel point is important both because of the factthat the gel's performance when applied in the body heavily depends onsuch parameter as well as due to the fact that it reflects the precisecomposition of the substance, thus constituting an important QCparameter to be measured in both R&D and production settings.

The determination of gel point for the above admixtures is essentialsince it is desirable that, in the context of the present invention, thegel point will not drop dramatically given that the lower the gellingtemperature, the more difficult will be to inject the compositionthrough a catheter into the body cavity.

Care should be taken concerning the active drugs that are used: In somecases, such as in Mitomycin C that is manufactured and distributed byKyowa Ltd., salts are added to the drug (for volume complementation) andthese salts change the viscosity—temperature dependence, so that thegelling point of the material is significantly lower. To avoid the lowergelling point, most DTCx materials use pure chemotherapy compounds,without added salts.

Flexibility to enable adherence through cycles of enlargement/reductionor flexing of muscles is an essential property of the material disclosedin the present invention. For example, the volume of the bladder whenDTCx material is instilled is 100 ml and when it is naturally filledwith urine—it can grow to 300 ml and even more. The present invention'sDTCx materials are designed to withstand such extreme cycles ofexpansion and collapse.

A range of compounds may be utilized to formulate a composition thatwill render the required properties as described in this invention.Non-limiting example of specific compositions utilized in the presentinvention are stated below.

In preferred embodiments of the invention, the material comprisespolymers and copolymers chosen from among the following: Polycarboxylicacids such as polyglycolic acid polylactic acid and polyacrylic acid;polyurethanes; polyesters such as poly(ethylene terephthalate);polyamides such as nylon; polyacrylonitriles; polyphosphazenes;polylactones such as polycaprolactone; polyanhydrides such aspoly[bis(p-carboxyphenoxy)propane anhydride; polyethylene; polyvinylchloride; ethylene vinyl acetate; Poloxamer block copolymers of the typePEGPPG-PEG; polyethylene oxide (polyethylene glycol); polypropyleneoxide(polypropylene glycol); polymethylacrylate; polysaccharides as dextrin,cyclodextrins, hydroxypropylmethylcellulose (HPMC),hydroxyethylcellulose, hydroxymethylcellulose, chitosan, polyvinylalcohol and polyvinyl acetate; Polylactide (PLA) andPoly(Lactide-co-Glycolide) (PLGA); polymer microspheres; starch andmodified starches; and cellulose polymers.

The medicament formulations according to the invention may comprise theactive ingredient in dissolved, suspended and/or solid, amorphous orcrystalline form. The active ingredient can be employed in variousparticle sizes, e.g. in unground, ground or in micronized form, toproduce the admix/formulation/mixture according to the invention withcontrolled release of active ingredient.

The admix/formulation/mixture described above with controlled release ofactive ingredient are for example in the form of activeingredient-containing hydrogels. These diffusion-controlled systems maybe completely diluted in the hydrogel admix/formulation/mixture or canbe multiparticulate, i.e. they may consist of a large number of coatedcores such as, for example, of microencapsulated APIs, where appropriatetogether with conventional excipients and carriers, as defined below forexample, is applied and subsequently coated with a diffusion coatingwhich may comprise plasticizers and other excipients. Thediffusion-controlled systems according to the invention may additionallyconsist of homogeneous active ingredient-containing cores which areproduced for example by granulation, rotor granulation, fluidized bedagglomeration, tableting, wet extrusion or melt extrusion, whereappropriate with spheronization, and are coated with a diffusion coatingwhich may comprise plasticizers and other excipients. In a preferredembodiment of this invention, the active ingredient-containing particlescomprise excipients such as, for example, acids or buffer substanceswhich modify the pH and thus contribute to reducing the dependence ofthe release of active ingredient on the pH of the release medium. In afurther preferred embodiment of this invention, the diffusion-controlledmembrane comprises excipients which, through their pH-dependentsolubility, influence the permeability of the membrane at different pHvalues and thus help to minimize the pH-dependence of the release ofactive ingredient.

The adhesive and thickening compounds preferably used in the productionof coated neutral pellets (e.g. consisting of sucrose, microcrystallinecellulose, citric acid) are polycarbophil (polymer of acrylic acidcrosslinked with divinyl glycol), hydroxypropylmethylcellulose (HPMC)and polyvinylpyrrolidone (PVP). It is likewise possible to employ othernaturally, synthetic or partially synthetic polymers such as, forexample methylcellulose (MC), hydroxypropylcellulose (HPC), otherhydroxyalkylcelluloses and hydroxyalkylmethylcelluloses,carboxy-methylcelluloses and salts thereof, polyacrylic acids,polymethacrylates, gelatin, starch or starch derivatives, as well asgums like guar gum and xanthan gum.

Bonding agents employed for the production of activeingredient-containing microcapsules are for example polycarbophil,cellulose, microcrystalline cellulose, cellulose derivatives such as,for example, HMPC, HPC and low-substituted hydroxypropylcellulose(L-HPC), dicalcium phosphate, lactose, PVP and sucrose, ethylcellulose,hydroxypropylmethylcellulose acetate succinate (HPMCAS), PVP,vinylpyrrolidone/vinyl acetate copolymer, polyethylene glycol,polyethylene oxide, polymethacrylates, polyvinyl alcohols (PVA),partially hydrolysed polyvinyl acetate (PVAc), polysaccharides (e.g.alginic acid, alginates, galactomannans) waxes, fats and fatty acidderivatives.

pH-modifying substances such as, for example, acids, bases and buffersubstances are incorporated into the active ingredient-containing core.Addition of these substances makes it possible to reduce markedly thepH-dependence of the release of the APIs. Examples of suitableexcipients which modify the pH in the active ingredient-containing coresare: adipic acid, malic acid, L-arginine, ascorbic acid, aspartic acid,benzenesulfonic acid, benzoic acid, succinic acid, citric acid,ethanesulfonic acid, 2-hydroxyethanesulphonic acid, fumaric acid,gluconic acid, glucuronic acid, glutamic acid, potassium hydrogentartrate, maleic acid, malonic acid, methanesulfonic acid,toluenesulfonic acid, trometamol, tartaric acid. Citric acid, succinicacid, tartaric acid, potassium hydrogen tartrate are preferablyemployed.

Particularly suitable for producing the diffusion coating areethylcelluloses and polymethacrylates such as, for example, EUDRAGIT®NE, EUDRAGIT® RS and RL. However, other materials such as, for example,cellulose acetate and cellulose acetate butyrate can also be employed asfilm-forming diffusion-controlling polymers.

Examples of plasticizers used are citric acid derivatives (e.g. triethylcitrate, tributyl citrate, acetyl triethyl citrate), phthalic acidderivatives (e.g. dimethyl phthalate, diethyl phthalate, dibutylphthalate), benzoic acid and benzoic esters, other aromatic carboxylicesters (e.g. trimellithic esters), aliphatic dicarboxylic esters (e.g.dialkyl adipates, sebacic esters, in particular diethyl sebacate,tartaric esters), glycerol monoacetate, glycerol diacetate or glyceroltriacetate, polyols (e.g. glycerol, 1,2-propanediol, polyethylene glycolof varying chain length), fatty acids and derivatives (e.g. glycerolmonostearates, acetylated fatty acid glycerides, castor oil and othernatural oils, Miglyol) and fatty acid alcohols (e.g. cetyl alcohol,cetylstearyl alcohol). The nature and amount of the plasticizer arechosen so that the above-defined release according to the invention andthe necessary stability of the medicinal forms is achieved. Theproportion of the plasticizer is from 0 to 50%, preferably 0 to 35%,particularly preferably 0 to 25% based on the mass of the hydrogelcomposition.

The release rate according to the invention is controlled by the gelcomposition. Certain components may increase the permeability of theadmix/formulation/mixture including water-soluble polymers such as, forexample, polyethylene glycols, PVP, PVA, HPMC, HPC,hydroxyethylcelluloses (HEC), MC, carboxymethylcelluloses or theirsalts, dextrins, maltodextrins, cyclodextrins, dextrans or other solublesubstances such as, for example, urea, salts (sodium chloride, potassiumchloride, ammonium chloride, etc.), sugars (sucrose, lactose, glucose,fructose, maltose etc.) and sugar alcohols (mannitol, sorbitol, xylitol,lactitol, etc.). Based on the mass of the hydrogel, from 0 to 50%,preferably 0 to 35%, particularly preferably 0 to 20%, increasingpermeability components may be employed.

A further aspect of the present invention are coatedadmix/formulation/mixture which comprise one or more swellableexcipients which, on penetration of liquid through the membrane, swellgreatly and, through the swelling and volume expansion, cause thecoating to split. The splitting of the coating makes it possible for themedicinal substance to be released from the admix/formulation/mixture,usually in pulsatile form. Swellable excipients which these formulationsmay comprise are, for example, polyvinylpyrrolidones, crospovidones,crosslinked sodium carboxymethylcellulose, crosslinked sodiumcarboxymethylstarch, polyethylene oxides, polymethyacrylates,low-substituted hydroxypropylmethylcellulose (L-HPC). Examples ofsuitable coating materials are cellulose acetate, ethylcellulose andpolymethacrylates.

The described diffusion-controlled or pulsatile formulations can beemployed directly and unmodified as medicinal form. However, they mayalso be further processed, where appropriate with addition ofexcipients, to the final admix/formulation/mixture. In order to achievea desired release profile it is also possible to combine differentcoated formulations in one medicinal form, and administration of aninitial dose can take place for example by combination withrapid-release formulation particles, e.g. uncoated pellets, granules orpowder.

In a further embodiment of the admix/formulation/mixture according tothe invention with controlled release there is use of formulations whichinclude the active ingredient in a admix/formulation/mixture. Thesegroup of admixes/formulations/mixtures release the active ingredient bydiffusion and/or erosion.

The mass ratio of active ingredient to the total mass of theadmix/formulation/mixture in these novel formulations is in the rangefrom 1:1 to 1:1000, preferably in the range from 1:2 to 1:100.

Admixes/formulations/mixtures which can be employed are water-soluble,water-swellable or water-insoluble substances. The novel formulationspreferably comprise one or more water-swellable polymers.

Preference is additionally given to medicinal preparations in thecontext of this invention which comprise water-soluble, hydrogel-formingpolymers, these polymers having a nominal viscosity of at least 0.015 Pas, preferably at least 0.050 Pa s (measured as 2% strength aqueoussolution at 20° C.).

A preferred family of candidates to be utilized as a basis for obtainingsaid hydrogel is group of tri-block copolymers designated as PEG-PPG-PEG(PEG=Polyethylene glycol and PPG=Polypropylene glycol) and calledPoloxamers, that produce reverse thermal gelaton compositions, i.e.,with the characteristic that their viscosity increases with increasingtemperature up to a point from which viscosity again decreases. Inparticular, Poloxamer 407 possesses a gelling temperature which is above10° C. but below the human body temperature, i.e., 37° C. Thischaracteristic may confer the ability of a composition containing thecompound to be injected or infused in liquid state into a bodily innercavity at a low temperature and, afterwards, as the composition warms,it becomes a gel, thus stabilizing upon the wall of the inner humancavity.

This characteristic has allowed PF-127 to be used as a carrier for mostroutes of administration including oral, topical, intranasal, vaginal,rectal, ocular and parenteral routes. In recent years PF-127 hasattracted particular interest in the design of dermal and transdermaldelivery systems, with a view to promoting, improving or retarding drugpermeation through the skin, bearing in mind that for topical deliverysystems, accumulation in the skin with minimal permeation is desired,while for systemic delivery, the opposite behavior is preferred.Poloxamer 407 (PF-127) is a nonionic surfactant composed ofpolyoxyethylene-polyoxypropylene copolymers in a concentration rangingfrom 20-30%. At low concentrations (10⁻⁴-10⁻⁵%) they form monomolecularmicelles, but higher concentrations result in multimolecular aggregatesconsisting of a hydrophobic central core with their hydrophilicpolyoxyethylene chains facing the external medium. Micellization occursin dilute solutions of block copolymers in selected solvents above thecritical micellar concentration, at a given temperature. At higherconcentrations, above a critical gel concentration, the micelles canorder into a lattice.

The non-limiting examples presented below illustrate the versatilitythat is provided by the diverse compositions, that allows itsengineering to render different release profiles, flow characteristics,instillation temperatures, coating layer thickness and additionalfeatures as required by the specific treatment to be applied upon aninternal cavity.

DTCx materials are inserted into the essentially empty bladder using acatheter. The material is inserted at low temperature in the range of10c to 100c, where the material viscosity is low enough to be able toflow freely into the bladder. As the liquid material flows into thebladder it is naturally heated by the body temperature and eventually itreached that temperature. When the material temperature reaches thegelation temperature—it is passes from the liquid phase to viscous gelphase. The present invention's method is designed to ensure thatmaterial will cover essentially most of the surface of the bladder andthat it will adhere to the bladder tissue at the point of contact.

In one preferred embodiment, a urinary catheter is used, such thatincorporates a large balloon with a volume of 70 cc to 140 cc. The coldand liquid material is inserted into the bladder after the bladder wasessentially emptied to minimize the amount of urine in the DTCx flow.The balloon is inflated to open the essentially collapsed bladder intoan essentially symmetrical shape that is not less than a quarter of thevolume of the bladder when it is filled with urine and reaches thevolume that may cause urge to void (micturition).

In a preferred embodiment, the catheter system includes means to measurethe momentary pressure that the balloon is applying on the bladder wallas indication for the physician to determine the level of inflating ofthe balloon. As a non-limited example, such means can measure thepressure of the liquid inside the balloon by connecting the supply tubeinto the balloon to a transparent column and reading the change inheights of liquid in that column as indication to the change in pressureon the bladder wall induced by inflating the balloon.

In a preferred embodiment, means are provided to make the flow out ofthe catheter exit from a hole positioned laterally close to the middleof the balloon.

In a preferred embodiment, means are provided to make the flow out ofthe catheter exit from the several holes set around the lateral middleof the balloon. The number of these exit holes can be between 2 and 4holes. Means are provided to ensure that the catheter can be insertedinto the urinary urethra in a known position, so that the position ofeach exit point is known. DTCx material is injected through the catheterin a number of doses that corresponds to the number of exit holes tocontrol the overall distribution of the material around the balloon.

In a preferred embodiment each exit hole has a separate tube leading toit and each dose is injected into a separate tube, so that gelatedmaterial inside that tube does not disturb the flow of the next dose.

In a preferred embodiment, the position of the patient is changed foreach dose so that each dose is injected separately between the inflatedballoon and downward toward the bladder wall—to utilize gravitation toassist material flow.

In a preferred embodiment means are provided to apply pressure on thematerial during its heating and gelation to help enhance its fixationand adhesion to the mucosal tissue of the bladder wall. In one preferredembodiment, the pressure is applied by the large balloon that is filledwith liquid such as water or saline. In another—the balloon can befilled with a heavier liquid such as saturated salt water (26%, withtypical density of 1.2 g/ml), or saturated solution of glucose in water.

In another preferred embodiment, the balloon contains magnetic materialembedded into its design; in another non-limiting example the catheterballoon can contain a metal rod. In yet another non-limiting example theballoon can be inflated with ferromagnetic liquid such as ferrofluids,made of finely divided magnetite (a form of iron oxide that isferromagnetic), an oily carrier and a surfactant like the compositionproduced by FerroTec, Inc—seehttp://www.ferrotec.com/products/ferrofluid/. In this example, thepressure is applied by an external magnet that is pulled to the magnetinside the balloon. The external magnet can be a stationary magnet andthe patient can be positioned against it corresponding to the exit holethat will be injected through. In another arrangement, the magnet can berotated around the patient. In another embodiment, the procedure can beadministered inside a system such as an MRI unit that enables rotatingthe magnetic field electronically.

In a preferred embodiment, the instillation of doses can be repeatedwith a similar or different set of materials to achieve a second layerof coating with additional properties, such as blocking layer that willreduce the diffusion of material into the bladder and slow the naturaldegradation of the material into the urine in the bladder. In anon-limiting example the similar materials can be the polymer ingredientof the DTC material such as a mixture of one or more of PEG-400, PEG-800or Poloxamer with distilled water. In a nonlimiting example, thismixture can be less viscous than the DTC material used for the firstlayer, thus having a slower diffusion rate and providing a barrieragainst release of drug into the bladder volume.

Following the instillation, the coating will release active ingredientswith medical effect on the bladder disease, such as cancer fightingdrugs that affect bladder cancer tumors. In parallel that coating willnaturally and gradually dilute into the bladder urine and be expelledduring urination.

In case it may become needed to speed this process of gradual dilutionby external actions, in a preferred embodiment, the coating can beremoved promptly by cooling the coating below its gelation temperature,thus significantly lowering its viscosity and speeding its dilution intothe bladder urine. In a non-limited example, the cooling can be affectedby flushing the bladder with a flow of cold liquid such as water orsaline through a regular catheter into the bladder. Water and Salinewill also help to melt water-based DTCx gels. In another preferredembodiment, the flow of cold liquid can be applied via a specialcatheter, which will enable a thin or focused jet of liquid that willexert pressure on a small part of the coating. In a preferredembodiment, the direction of this jet may be changed such that it can beactivated on several areas of the bladder coating sequentially.

In another preferred embodiment, speeding the removal of the coating canbe achieved by applying a chemical agent such as a solvent that canassist in the dissolution of the coating. The chemical agent can bechosen according to the formulation of the DTCx. As a non-limitingexample, ethyl or isopropyl alcohol and DMSO (dimethyl sulfoxide) can beused to dissolve coatings that include lipophilic materials.

The versatility of the polymer composition and the ability to controlits physicochemical properties may allow the incorporation and optimizesustained-release dosing of additional active ingredients that may bedesired in a chemotherapy treatment, including the reduction of pain,avoidance of inflammation and other undesired effects. Thus, besides theactive ingredients that serve as chemotherapy agents, other drugs can beincorporated in the gel composition, among them anesthetic drugs (e.g.,lidocaine), coagulants (e.g., proconvertin) anticoagulants (likeheparin), anti-inflammatory drugs (steroidal and non-steroidal) andothers, according to the medical requirements for patients suffering ofSBC utilizing the effect of gradual release of the diverse activecomponents for an optimal treatment.

According to another embodiment of the present invention, other drugscan be incorporated in the gel composition. Such drugs can beadministered topically and can belong to at least one of the followingfamilies: Antineoplastic drugs; Chemotherapeutic agents; Anti-infectiveagents (Antimicrobial drugs, Antiparasitic agents, Antivirals); Drugsacting on the blood and blood forming organs (Antihemorrhagics,Antithrombotic agents, antianemic drugs); Dermatologic drugs(antifungals, antiseptic); Genito-urinary system drugs; Gastrointestinalsystem (antiobesity, acid related disorders); Metabolism drugs;Anti-inflammatory product; Musculoskeletal system acting drugs;Neurological drugs; Respiratory drugs; Cardio-vascular drugs; Otologicaldrugs; Anti-infective drugs; Corticosteroids drugs; Analgesics andanesthetics drugs; Antiparasitics drugs or any combination thereof.

According to another embodiment of the present invention, other drugscan be incorporated in the gel composition. Such drugs can be selectedfrom a group consisting of, Antibacterials/Antibiotics,Antiinflammatories/Corticosteroids, Antineoplastics/Cytotoxics, Growthfactors such as VEGF (Vascular Endothelial Growth Factor) and Inhibitoryfactors such as LIF (interleukin 6 class cytokine).

According to another embodiment of the present invention, at least oneof the following is utilized in the admix/formulation/mixture: Poly(propylene oxide)—PPO, Poly (lactide-co-glycolic acid)—PLGA, Poly(N-isopropylacrylamide)—PNIPAM, Poly (propylene fumarate)—PPF, Poly(urethane)—PU, Poly (organophosphazene)—POP, Poloxamers of the typePEO-PPO-PEO (Poly (ethylene oxide), Poly (propylene oxide), Poly(ethylene oxide)) such as poloxamer 68, 88, 98, 108, 124, 127,188, 237,338 and 407, Stearic Acid, Poly (acrylic acid), Glyceryl Stearate,Cetearyl Alcohol, Sodium Stearoyl Lactylate, Hydroxy-Lenolin or anycombination thereof.

According to another embodiment of the present invention thehydrogel\polymer composition may includes active pharmaceuticalingredients (APIs) that are expected to render a better therapeuticperformance at lower risk levels. Specifically, the anticancerous drugmitomycin C (MMC) has been experimentally utilized in in vitro settingsand applied on the internal bladder wall of animal specimens. The API isreleased in a controlled manner and the residence time inside thebladder is in the order of up to 24 hours instead of the accustomed 1-2hours (until micturition).

According to another embodiment of the present invention theadmix/formulation/mixture as provided above, can be used as biologicalglue so as to glue at least two tissues together. By adjusting theviscosity of the admix/formulation/mixture such biological glue can beprovided.

It is a further object of this invention to disclose such a method asdefined in any of the above, wherein the weight of the balloon filledwith a liquid denser than water is used for the application of the gel(utilizing its gravity).

It is a further object of this invention to disclose such a method asdefined in any of the above, wherein said step of applying force to saidmaterial further comprises a step of filling said catheter balloon withwater and positioning the patient to utilize the gravitational forcesdirectly toward the target tissue during the solidification of thematerial and cause optimal adhesion to that target tissue.

It is a further object of this invention to disclose such a method asdefined in any of the above, wherein said step of applying gravitationalforce to said material further comprises a step of changing the positionof the patient before applying partial doses of material to enablesubstantially full coating of the whole targeted internal cavitysurface.

According to another embodiment, the material is used not only forcoating internal cavities but rather coating organs selected fromurinary bladder, mouth, nasal and paranasal sinus, gallbladder,esophagus, rectum, lungs, vagina, uterus, stomach, renal pelvis, pleura,abdomen, peritoneum, pelvis, liver, kidney, heart, intestine, brain,vertebral column, or any combination thereof.

In order better to illustrate how the invention may be put intopractice, the following non-limiting examples of some of the embodimentsof the invention are now provided.

Example 1

The effectiveness of the present invention hydrogel composition drugdelivery to the urinary tract is demonstrated by the followingpre-clinical example. Two embodiments of reverse thermal gelation,mucoadhesive and flexible hydrogel mixed with MMC (Kyowa) at aconcentration of 1 and 2 mg/ml were prepared as follows.

DTC1: The material comprised Pluronic F-127 Ethylene Oxide/PropyleneOxide Block Copolymer (27.0%); Polyethylene glycol, average MW=400(PEG-400) (1.0%); Hydroxypropylmethyl cellulose (HPMC) (0.2%); with theremainder water for injection (71.8%) was mixed with MMC (Kyowa) at aconcentration of 1 mg/ml.

DTC2: The material comprised Pluronic F-127 Ethylene Oxide/PropyleneOxide Block Copolymer (27.0%); Polyethylene glycol, average MW=400(PEG-400) (1.0%); Hydroxypropylmethyl cellulose (HPMC) (0.2%); with theremainder water for injection (71.8%) was mixed with MMC (Kyowa) at aconcentration of 2 mg/ml.

DTC1 and TDC2 were intravesically instilled in pigs. The MMCconcentration in tissue was measured using HPLC and compared tointravesical instillation of 1 mg/ml MMC in water (standard treatment ofNon-Muscle Invasive Bladder Cancer; Total MMC dosage of 40 mg). Inaddition, bladder condition following instillation and in-vivo geldissolution rate were evaluated.

Higher MMC tissue concentrations were obtained following DTC1 and DTC2hydrogels treatments in comparison to the standard control treatment(MMC in water). Two hours following intravesical treatment of DTC1 theMMC concentration in urithelium tissue was 11 fold higher for the DTC1in comparison to that of the control treatment (1 mg/ml MMC in water).The MMC concentration following intravesical treatment of DTC2 was 1.8fold higher than that obtained for TC-3+1 mg/ml MMC. MMC tissueconcentration 6 hr following instillation of DTC1 was 13 fold higherthan that of the control treatment. Similar average MMC concentrationswere obtained for DTC1 and DTC2. No damages to the urotheliumcontiguity, or bladder wall perforation were observed. The ureters andurethras were intact. No sign of ureter or urethral obstruction wasobserved. No clinical effects on animal's vital parameter were detectedduring the complete treatment duration. In addition, residues of MMChydrogel were observed in the pig bladder 6 hrs following instillation,supporting release duration of more than 6 hr.

Example 2

One embodiment of the material disclosed in the present invention(DTC-1) that incorporates the active therapeutic agent Mitomycin C (MMC)was prepared as follows. The material comprised Pluronic F-127 EthyleneOxide/Propylene Oxide Block Copolymer (27.0%); Polyethylene glycol,average MW=400 (PEG-400) (1.1%); Hydroxypropylmethyl cellulose (HPMC)(0.2%); MMC (0.1%); with the remainder (71.6%) double distilled water.DTC-1 has an instillation temperature of 30° C.; a sustained releaseduration of 12 hours; and a degradation time (until fully expelled fromthe body) of <24 hours.

Example 3

A second embodiment of the material disclosed in the present invention(DTC-1) that incorporates the active therapeutic agent Mitomycin C (MMC)was prepared as follows. The material comprised Pluronic F-127 (27.0%);PEG-400 (1.1%); HPMC (0.2%); MMC (0.2%); with the remainder (71.5%)double distilled water. DTC-2 has an instillation temperature of 50° C.;a sustained release duration of 16 hours; and a degradation time (untilfully expelled from the body) of <24 hours.

Example 4

A third embodiment of the material disclosed in the present invention(DTC-3) that incorporates the active therapeutic agent Valrubicin wasprepared as follows. The material comprised Pluronic F-127 (27.0%);PEG-400 (1.1%); IPMC (0.3%); Valrubicin (0.1%); with the remainder(71.6%) double distilled water. DTC-3 has an instillation temperature of50° C.; a sustained release duration of 18 hours; and a degradation time(until fully expelled from the body) of 18 hours.

The increase in the amount of IPMC reduces the release rate from thecarrier composition.

The dominant release parameter will be the composition dilution in theurine medium. The therapeutic agent is gradually released during thetime until the composition is totally expelled from the body.

Example 5

A fourth embodiment of the material disclosed in the present invention(DTC-4), designed to have faster release and expulsion rates and whichincorporates the active therapeutic agent MMC, was prepared as follows.The material comprised Pluronic F-127 (27.0%); PEG-400 (1.8%); IPMC(0.2%); MMC (0.1%); with the remainder (70.9%) double distilled water.DTC-4 has an instillation temperature of 30° C.; a sustained releaseduration of 10 hours; and a degradation time (until fully expelled fromthe body) of <16 hours.

The decrease in the amount of PEG-400 increases the release rate fromthe carrier composition and the composition's dilution in the urinemedium. In this case, drug is released more rapidly and the compositionis totally expelled from the body within 16 hours.

Example 6

A fifth embodiment of the material disclosed in the present invention(DTC-5) that incorporates lidocaine was prepared as follows. Thematerial comprised Pluronic F-127 (27.0%); PEG-400 (1.8%); HPMC (0.2%);Lidocaine 25 mg/10 ml composition (0.25%); with the remainder (70.75%)double distilled water. DTC-5 has an instillation temperature of 60° C.;a sustained release duration of 24 hours; and a degradation time (untilfully expelled from the body) of 24 hours.

Example 7

A sixth embodiment of the material disclosed in the present invention(DTC-6) that incorporates the therapeutic agent MMC was prepared asfollows. The material comprised Pluronic F-127 (27.0%); PEG-400 (1.1%);HPMC (0.2%); MMC (0.25%); with the remainder (71.35%) double distilledwater. DTC-6 has an instillation temperature of 30° C.; a sustainedrelease duration of 18 hours; and a degradation time (until fullyexpelled from the body) of 24 hours.

Example 8

A seventh embodiment of the material disclosed in the present invention(DTC-7) that incorporates the therapeutic agent Gemcitabine HC1 wasprepared as follows. The material comprised Pluronic F-127 (25.0%); IPMC(0.2%); Gemcitabine HC1 25 mg/10 ml composition (0.25%); with theremainder (74.%) double distilled water. DTC-7 has an instillationtemperature of 20° C.; a sustained release duration of 12 hours; and adegradation time (until fully expelled from the body) of <18 hours.

It should be clarified that the above compositions refer to the use ofchemically pure drugs. Commercially, some of the drugs are provided asadmixtures of the active ingredient and other non-active compounds. Forexample, MMC is provided commercially in ampoules that contain 0.1 mgMMC and 240 mg sodium chloride, which provide an isotonic solution whendissolved in 10 ml double distilled water. The presence of salts assodium chloride in the final material may have a considerable effect inthe composition's physicochemical properties, among them and not limitedto viscosity and gelation temperature, which are critical in theapplication method. These filler materials must be considered whenformulating the different compositions, which should be adapted to theactual formulation of the active ingredient and its excipients.

Example 9

An in-vitro study was performed to evaluate the efficacy of DTCxmaterials as cytotoxic agents in the urinary bladder. A carcinoma cellline was treated with MMC incorporated into the material disclosed inthe present invention, and the results the treatment were compared totreatment with MMC dissolved in saline. Viability was assessed by MTTassay which tests mitochondrial function.

Cell lines of human bladder cancer were grown in RPMI 1640 medium,supplemented with FBS, 100 U/ml penicillin and 100 mg/ml streptomycin.At Day 1 cells were seeded in 24-well plates at a MMC concentration of1×10⁴ (four replicates for each concentration, 1 plate for each analysistime). The cells were then exposed for 24 hours to DTC-2; in separateexperiments, DTC-2 samples that contained 0.05, 0.1, 0.5 or 1 μg/ml MMC(Kyowa, Hakko Kogyo Co. Ltd.) were used. After 2 hours of incubation,medium was replaced with fresh medium for all plates.

The plates were tested by taking out the medium and adding fresh mediumcontaining MTT reagent. All other plates were returned to the incubatorfor incubation of 24, 72, 120 and 144 h. MTT assays were used to assesstoxicity at all time points. The proportion of living cells wascalculated by comparison to the control vehicle.

A microplate reader (EL 312e: Bio-Tek Instruments, Winooski Vt.) wasused to evaluate the presence of LDH as a color development measured byabsorbance spectroscopy at 450 nm. Background optical density (OD) wassubtracted from the OD readings of all samples. Cell viability wascalculated by dividing the mean OD absorbance values of the treatedwells by the mean OD absorbance of the control wells. All samples weretested in triplicate.

Reference is now made to FIGS. 3A-3D, which show graphs of cellviability as a function of time for various experiments. These resultsclearly demonstrate MMC cytotoxicity when different MMC concentrationsare used in saline and in TC-2 respectively.

These studies clearly demonstrate that a dramatic effect may be observedin the case of 0.1 μg/ml (see FIG. 3A) where the difference between theeffect of the DTC-2 hydrogel and that of the MMC-saline solution is mostpronounced. For MMC-saline solution, there is practically no cell-kill,while with DTC-2 the cell-kill effect reaches 60%.

A direct relationship was demonstrated between MMC time of exposure andcytotoxicity. As seen in the graphs, in practically all cases thegeneral trend is that the cytotoxicity increases as exposure timeincreases.

A direct relationship was also demonstrated between MMC concentrationand cytotoxicity. Comparing the graphs obtained for differentconcentrations shows a higher cytotoxicity effect with the increase ofconcentration.

Thus, higher concentrations of MMC and longer exposure time contributesignificantly to a higher cytotoxicity of MMC. When exposure time wasincreased from 2 hours to 24 hours, a cell kill level was achieved withless than one third of the MMC dose used for two hours exposure.

MMC concentrations in intravesical instillations have been evaluated inmany different studies. Current treatment concentration is the highestthat can be tolerated by the patient. Our results demonstrate that afurther improvement in MMC efficacy can be gained by increasing theexposure time to MMC even at lower MMC concentrations.

Example 10

The inventors of the present invention conducted a preclinical trialwith sick female mice model testing the DTCx material (TC-1 polymer andGemzar chemotherapy) on a MBT-2 disease model. These tumors areextremely aggressive and resistant to chemotherapy therefore somewhatdiffer from human superficial bladder cancer. In this study, treatmentwas applied 14, 10, and 3 days following cell implantation. Each groupwas divided into a DTCx material arm and a standard instillation armconsisting of Gemzar in saline, which served as control group. Theresults showed that the procedure was safe (indeed, with low mortality)and efficient, that is, consistent lower weights of cancerous bladder inthe DTCx arm were obtained as compared to the control arm.

Large animal safety and efficacy studies were conducted on female pigs.The results demonstrated excellent control and no catheter-related ormethod-related adverse events.

The safety of the present invention's material and procedure bycomparing the outcome of one week follow-up of animals following DTC-2instillation to standard MMC instillation—seeking short & medium termadverse events (urinary retention, urethral obstruction, toxicity—bothlocal and systemic).

Comparison of MMC concentrations in bladder tissue at 12 hours followinginstillation versus standard 2-hour instillation has demonstratedsignificantly higher MMC concentration in the bladder tissue for theprocedure of the present invention, demonstrating the improved efficacyof the material and method disclosed in the present invention relativeto methods known in the art for applying MMC to bladder tissue.

Example 11

Studies performed by the inventors demonstrate that controlled releaseof the drug can be obtained which considerably prolong the actualcontact between the bladder wall and the drug. This slow-release effect,which can take between 16 and 24 hours, dramatically increases suchcontact time and thus the continuous therapeutic effect of the drug uponthe cancerous tissue. This effect, in tandem with the creation of aneffective, stable coating upon the bladder wall, is expected to render asuperior therapeutic effect in the treatment of bladder cancer.

In vitro studies performed by the inventors showed a gradual release ofthe drug embedded in the polymer composition in conditions similar tothose of a human bladder (37° C., urine medium). The drug was graduallyreleased throughout the tests over the course of 12-24 hours.

Further in vitro studies performed by the inventors show a gradualrelease of the drug embedded in the polymer composition in conditionssimilar to those of a human bladder (37° C., urine medium) when insteadof continuously exposing the polymer composition to one portion ofurine, such urine is changed every two hours and fresh portions replacethe older ones during 24 hours. It was again found that the drug wasgradually released throughout the tests during 16-24 hours.

A parallel set of in-vitro release experiments were performed usingmembraneless dissolution model: The hydrogel was loaded with the testeddrug, layered in a glass containers, and equilibrated in theexperimental temperature until homogenous gel layer was formed. acceptorsolution was discarded every hour and replaced by a fresh solution. Drugconcentration in acceptor solution was measured spectrophotometrically,gel dissolution was determined gravimetrically. Two examples areprovided here.

a. Reverse thermal gelation hydrogel composed of Pluronic F-127 EthyleneOxide/Propylene Oxide Block Copolymer (27.0%); Polyethylene glycol,average MW=400 (PEG-400) (1.0%); Hydroxypropylmethyl cellulose (HPMC)(0.2%); and the remainder water for injection (71.8%) was loaded with ata concentration of 10 mg/ml and 20 mg/ml Lidocaine hydrochloride.

The in vitro release of Lidocaine hydrochloride (10 and 20 mg/ml) fromthe hydrogel formulation enclosed above is shown in FIG. 7 . Thereleased amount of Lidocaine hydrochloride was twofold higher forhydrogel loaded with 20 mg/ml Lidocaine hydrochloride in comparison tothe hydrogel loaded with 10 mg/ml Lidocaine hydrochloride formulation.In addition, higher amount of Lidocaine hydrochloride was released fromboth formulations to the acceptor solution in the first testing timepoint (1 hr). The amount of Lidocaine hydrochloride released in thefollowing time points was relatively constant.

b. Reverse thermal gelation hydrogel composed of Pluronic F-127 (20.0%);Pluronic F-68 (10.0%) Polyethylene glycol, average MW=400 (PEG-400)(1.0%); carboxymethyl cellulose sodium (CMC) (0.4%); and the remainderwater for injection (68.8%) was loaded with at a concentration of 1mg/ml cephalexin.

The in vitro release of cephalexin (1 mg/ml) from the hydrogelformulation enclosed above is shown in FIG. 7 . The results demonstrateconstant release of cephalexin at 3-6 hrs.

Example 12

Studies were performed on the adhesiveness of the material of thepresent invention to mucosal tissue. Remarkable, unexpected results wereobtained.

Adhesiveness was measured by the “rolling ball” method according to theASTM D-3121-94 and PTSC-6 standard methods. In these experiments, theadhesiveness of the material disclosed in the present invention wascompared to the adhesiveness of compositions disclosed in U.S. Pat. Nos.6,207,180; 6,894,071; and U.S. Pat. Appl. US2006/0127210. The resultsindicate that the material is potentially suitable for use as a drugcarrier for the treatment of bladder cancer. The results are summarizedin Table 2 and show a difference of at least 20 times in adhesive power.

TABLE 2 Test 1 Result Test 2 result Composition (cm) (cm) U.S. Pat. No.6,207,180 32 20 U.S. Pat. No. 6,894,017 >45 >28 U.S. Pat. Appl.2006/0127420 >45 >28 present invention 1.0 1.6

Example 13

A second comparative study was performed in which the adhesiveness ofthe material of the present invention to biological material wascompared with those of the three compositions cited in the previousexample. The tests were performed according to ASTM standard D-225603,which determines adhesiveness by measuring peel strength. Adhesiveproperties were assessed applying equal amounts of the four compositionsto biological tissues. Different types of loads were subjected to thesamples, in order to mimic conditions occurring during in vivoapplications. To standardize the test results, with respect to themultiplicity of applications and of tissues treated, pig bladder tissuewas used as the unique substrate. The results are summarized in Table 3.

TABLE 3 Adhesiveness Composition (N/cm²) U.S. Pat. No. 6,207,180 0.068U.S. Pat. No. 6,894,017 0.047 U.S. Pat. Appl. 2006/0127420 0.090 presentinvention 1.77

These results demonstrate that the material of the present invention isat least 20 times more adhesive to biological tissue than the materialsknown in the prior art.

Example 14

A second set of in vitro tests of the bioadhesive properties of thematerial disclosed herein was performed. These tests were performed onfresh female swine bladder using a TAXT2 texture analyzer according tothe following protocol.

A tissue specimen was placed on a foam tape mounted onto the cylindricalsupport of the instrument (2 cm diameter and 4 cm length) and securedwith a string. The whole support was then positioned at the top of themeasuring system and held in place by a clamp. A given weight ofhydrogel (for example, 0.5 g) was evenly poured onto another support ofsimilar dimensions. The support was then affixed on the lower probe ofthe instrument. The two supports were aligned to ensure that the gelcomes into direct contact with the surface of the swine tissue when theupper support is lowered. Measurements were performed at 25° C.

Before measurement, 100 μl of simulated urine fluid was evenly spread onthe surface of the tissue. The upper support was then lowered at a speedof 0.5 mm/s to contact with the gel at a force of 1 N for a contact timeof 10 s. It was then withdrawn at a rate of 1.0 mm/s to a distance of 10mm. An acquisition rate of 200 points/s was chosen for the analysis.Data collection and calculation can be performed using the XTRADimension software package of the instrument. The work of adhesion andpeak detachment force were used to evaluate the bioadhesive strength ofthe films. The work of adhesion is calculated from the area under theforce-distance curve, and the peak detachment force is taken as themaximum force needed for detaching the film from the tissue. Allmeasurements were performed in triplicate. The results are summarized inTable 4.

TABLE 4 Double Work of Peak Form- Pluronic PEG Distilled AdhesionDetachment ulation F127 HPMC 400 Water (mJ) Force (N) A 25.0% 0.1% 0.5%balance 0.51 3.34 B 27.0% 0.1% 1.0% ″ 0.73 4.43 C 27.0% 0.2% 1.0% ″ 1.136.35

A marked increase in the bioadhesion strength was observed with anincrease in HPMC content.

Example 15

Gel point measurements were made for a number of embodiments of thematerial herein disclosed. The general procedure for the measurementswas as follows. First, 50 ml of the material was poured into a 100-mlglass container. A TEFLON-coated magnet of 2-2.5 cm length was thenplaced in the container. A thermocouple was then inserted into the bulkof the hydrogel. The container was placed in an ice bath on a magneticstirrer plate. After the temperature of hydrogel dropped to 5° C., theice bath was removed from the magnetic stirrer and the glass containercontaining the hydrogel was placed directly on top of the magneticstirrer plate. The magnetic stirrer was then turned on and run at mediumspeed (120 rpm). The temperature was allowed to rise gradually (˜1°C./min) to room temperature. The gel point for a particular measurementwas recorded as the temperature at which the magnet stopped rotating.For each sample, the entire procedure was performed twice, and the gelpoint determined as the average of the two measurements.

The gel point was measured for three different embodiments of thematerial disclosed herein. The results of the measurements aresummarized in Table 5.

TABLE 5 Double Pluronic PEG Distilled Gel Point Formulation F127 HPMC400 Water (° C.) A 25.0% 0.1% 0.5% balance 16.5 B 27.0% 0.1% 1.0% ″ 14.1C 27.0% 0.2% 1.0% ″ 11.9

A further set of tests was performed in which MMC was incorporated intothe material at a typical dosage concentration in order to determine theeffect of the MMC (and its accompanying excipient) on the gel point ofthe final composition. Formulation D includes pure MMC; formulation Eincludes commercially obtainable MMC that includes 2 parts mannitol per1 part MMC (for example, Boehringer Mannheim) and Formulation F includes24 parts of sodium chloride per 1 part MMC (for example, Kyowa). Theresults are summarized in Table 6.

TABLE 6 Double Gel PEG Distilled Point Formulation Pluronic F127 HPMC400 MMC NaCl Mannitol Water (° C.) D 27.0% 0.2% 1.0% 0.1% 0 0 balance11.8 E 27.0% 0.2% 1.0% 0.1% 0 0.2% ″ 11.5 F 27.0% 0.2% 1.0% 0.1% 2.4% 0″  5.1

As can be seen, incorporation of NaCl into the commercial MMCsignificantly lowers the gel point while mannitol does not affect thegel point very much. The major drop in gel point produced by NaCl ascompared to that of mannitol can be explained by (a) the fact that theconcentration of NaCl is significantly larger and (b) NaCl is aninorganic salt, thus releasing a number of moles of ions that is twicethe number of moles of the original NaCl. The drop in gel point due tothe addition of MMC itself is insignificant for practical purposes.

In addition to the gelation point of the reverse thermal gelationhydrogel its viscosity as a function of temperature is an importantfeature that determines the hydrogel's behavior and ability to performproperly. Therefore the rheological properties of formulation candidateswere studied. The viscosity vs temperature curves and values of Tg(gelling temperature) for each formulation were determined by RV DV IIIBrookfield rheometer and DVII LV viscometer. The temperature at which asharp increase in viscosity was obtained was determined as Tg. Theviscosity measurement of the solid state of the gel (after completesolidification) was out of the range of the used rheometer andviscometer.

Reference is now made to FIG. 5A, which presents a semi-logarithmicgraph of viscosity as a function of temperature over a range of 5-35° C.for six different embodiments of reverse thermal hydrogels disclosed inthe present invention composition for effective drug delivery (TCA, TCB,TCC, TCD, TCE, TCF), and Table 7, which presents the results of a samplegel point measurements.

TABLE 7 Form- Pluronic Pluronic Gel ulation F127 F68 HPMC CMC PEG-400Point TCA 27.0% — 0.2% — 1.0% 15° C. TCB 20.0% — 0.2% — 1.0% 22° C. TCC20.0% 10.0% 0.2% — 1.0% 33° C. TCD 25.0%  5.0% 0.2  1.0% 17° C. TCE20.0% 10.0% — 0.4% 1.0% TCF 20.0% — — 0.2% 1.0% 20° C.

This information is fundamentally important for the design andengineering of the hydrogel device since viscosity characteristics arecritical in the gel flow through the catheter and spreading upon thebladder inner surface as it is injected by means of the catheter.

Example 16

One of the main features that determines the hydrogel's behavior andability to perform properly is its viscosity as a function oftemperature. Therefore the rheological properties of formulationcandidates were studied, including viscosity as a function oftemperature and determination of gelling temperature (Tg).

The viscosity vs temperature curves and values of Tg (gellingtemperature) for each formulation were determined by means of an AR1000-N Rheolyst rheometer (TA Instruments). The determination of Tg wasdetermined through the crossover of the G′ (elastic modulus) and G″(viscous modulus) curves (see graph below the curves for TC-A).

Reference is now made to FIG. 5A, which presents a semi-logarithmicgraph of viscosity as a function of temperature over a range of 4-50° C.for four different embodiments of the material herein disclosed (TCA,TCB, TCC, TCD), and to FIG. 5B, which presents the results of a samplegel point measurements. The formulations of the four embodiments aresummarized in Table 8.

TABLE 8 Formulation Pluronic F127 HPMC PEG-400 Gel Point TCA 27.0% 0.2%1.0% 11.9° C. TCB 25.5% 0.2% 1.0% 14.5° C. TCC 25.5% 0.15% 1.0% 14.8° C.TCD 23.0% 0.15% 0.5% 22.3° C.

Interestingly, increase in viscosity with temperature in the lowtemperature range is approximately logarithmic. As can be seen in thegraph, even minor modifications of the same basic formulation canproduce substantial changes in the rheological behavior of the product.

For TC-A, the values of viscosity in the temperature range of interestare 16 Pa s at 10° C., which is the temperature at which the gel (whichat that temperature is still in liquid form) is expected to be cooledbefore application upon the bladder wall; and 4,600 Pa s at 37° C.,which is the gel's final temperature (body temperature). As explainedbelow, the method utilized allowed the determination of the gel point aswell.

This information is fundamentally important for the design andengineering of the catheter/hydrogel device since viscositycharacteristics are critical in the gel flow through the catheter andspreading upon the bladder inner surface as it is injected by means ofthe catheter.

Example 17

According to another embodiment, the mixture of gels obtained, accordingto the present invention, adhere well to the inner surface of humancavities, by their inherent reverse thermal gelling properties.Furthermore, they release the drug in a controlled way and that theythemselves (the gels) gradually degrade so that they are expelled fromthe body in up to 24 hrs.

The following are further examples of mixtures according to the presentinvention:

17.1—Vitamin gel for topical action provided, according to thefollowing:

Vitamin (A, D or K) 0.05% w/w Lecithin 12% PEG 800  1% Isopropylstearate  8% Pluronic F-127 20% Double distilled water (DDW) to 100%   

17.2—Paclitaxel gel for cancer treatment, according to the following:

Paclitaxel 0.1% Pluronic F-127 10.0%  Isopropyl Palmitate   1.0% sLecithin 0.8% Sodium Acryloyldimethyl 1.2% Taurate Copolymer Sorbic Acid1.0% Potassium Sorbate 0.1% DDW to 100%  

17.3—Oral anesthetic gel, according to the following:

Lidocaine 1.0% Pluronic F-127  27% Ethoxyl diglycol  10% Lecithin 2.0%Mint flavor 0.1% DDW to 100%  

17.4—Anti-inflammatory composition, according to the following:

PEG-PLGA-PEG* 24.5%  HPMC 0.2% PEG 400 0.5% Ibuprofen 0.2% DDW to 100%  *Ethylene glycol-lactic acid-co-glycolic acid-ethylene glycol triblockcopolymer

17.5—Antibacterial gel, according to the following:

PEG 400 1.5% PEG 1200 12.0%  Polysorbate 60  6% Pluronic F-127  22%Polyvinyl pirrolidone - iodine complex 5.5% DDW to 100%  

17.6—MMC gel, according to the following

Pluronic F-127  20% Carboxymethyl cellulose sodium 0.5% PEG 400  1% MMC0.2% In 50 mM Tris-HCL buffer pH = 8 to 100%  

17.7—Botox gel, according to the following

Pluronic F-127    20% Carboxymethyl cellulose sodium   0.4% PEG 400   1%Botox 5 U/gr In 50 mM buffer acetate pH = 5 to 100%

Example 18

The effect of PEG-400 concentration on the gelation temperature wastested. The gelation temperature was determined at the temperature atwhich a sharp increase in the viscosity was observed (viscosity atgelation >106 mPa s) in a Brookfield rheometer DV-III, spindle 52. Theresults are summarized in Table 9.

TABLE 9 Gelation temperature Formulation HPMC PEG-400 Pluronic F127 (°C.) a 0.2 1 27 15 b 0.2 10 27 6

Example 19

The effect of HPMC concentration on the gel viscosity was measured.Viscosity measurements were performed using a Brookfield rheometerDV-III, spindle 52, at 6° C., and represent the viscosity of theformulation in its liquid state. The results are summarized in Table 10.

TABLE 10 HPMC PEG-400 Pluronic F127 Viscosity Formulation (% w/w) (%w/w) (% w/w) (mPa s) 1 0.2% 1 27 223 2 0.5 1 27 357 3 1.5 1 27 603 4 0.21 20 96 5 0.5 1 20 431 6 1.5 1 20 5742

Example 20

A gel composition according to the present invention was used fordelivery of Mitomycin C (MMC) to pig bladder. MMC was incorporated intoa gel containing 0.2% (w/w) HPMC, 1% (w/w) PEG-400, 27% (w/w) PluronicF127 in water. In one experiment, the MMC concentration in the gel was 1mg/ml (total dosage 40 mg); in another, the MMC concentration was 2mg/ml (total dosage 80 mg). In each case, as a control, MMC wasdelivered from a solution containing MMC in the same concentration as inthe analogous gel. The experimental results are summarized in FIG. 6 .

As can be seen in the figure, higher MMC tissue concentrations wereobtained following application of MMC contained in a gel of the presentinvention than by using a solution of MMC. Two hours followingintravesical treatment by gel containing 1 mg/ml MMC, the MMCconcentration in the tissue was 11 times higher than in the control. TheMMC concentration in the tissue following application of gel with 2mg/ml was 1.8 times higher than that in the experiment in which theconcentration was 1 mg/ml. Six hours following treatment by gelcontaining 2 mg/ml MMC, the tissue MMC concentration was 13 times higherthan in the control.

Example 21

An additional example for the effective drug delivery to the urinarytract of the present invention composition was demonstrated by apreclinical study testing the delivery of botullinium toxin A (BoNT-A)to rats bladder induced with chronic cystitis.

The effect of BoNT-A mixed with one embodiment of the invented materialDTC-4 on bladder cystitis was demonstrated in a rat model(Sprague-Dawley) by comparing the effect of intravesical administrationof BoNT-A in saline and in gel. The BoNT-A gel formulation (DTC-4)tested included 20 U BoNT-A/ml gel composed of 27% Pluronic F127, 0.2%HPMC and 1% PEG-400 in water. Intravesical instillation of just DTC-4and of saline with no botullinium toxin served as control groups.Chronic cystitis was induced by intraperitoneal injection ofCyclophosphamide (75 mg/kg was injected on day 1, 4 and 7). On day 2PE-50 tubing was inserted into the rat bladder through the urethra. Thebladder was emptied of urine and filled with DTC-4 or saline with andwithout BoNT-A (1 ml, 20 u/ml Allergan). On day 8 the animals wereanesthetized and their bladders were examined by cystometrogramrecording via PE-50 tube inserted into the bladder dome. After recoverythe animals were gently restrained and the suprapubic catheter wasconnected to infusion pump (0.08 ml/min continuously) and pressuretransducer for recording intravesical pressure and for saline infusioninto the bladder to elicit repetitive voiding. The amplitude and theinter-contraction interval of reflex bladder contractions were recorded.Each tested groups included 2-4 rats.

The bladder contraction amplitude measured is shown in FIG. 4A. Theresults demonstrate that following CYP administration the bladdercontraction amplitude increased from 25-27 mmHg (contraction level forrat bladder with no hyperactivity) to about 42 mmHg Followingadministration of BoNT-A in saline and in TC-3 gel to rats with inducedchronic cystitis the contraction decreased to the baseline levelamplitude of 30 mmHg and 24 mmHg, respectively. Better response wasreceived for the BoNT-A in gel treatment demonstrating the activity ofthe BoNT-A in gel and efficacy of BoNT-A mixes with gel treatment.

Similar results were obtained for the measurements of bladderinter-contraction intervals summarized in FIG. 4B. Following CYPadministration the bladder inter-contraction intervals were shown todecrease from 4-5 min for rat administered with saline or gel to 2 min.Intravesical administration of BoNT-A in saline and in TC-3 gel to ratswith induced chronic cystitis increased the inter-contraction intervalsto about 4 min, close to the inter-contraction intervals for bladderwith no hyperactivity. These results further support the activity of theBoNT-A in the gel and the efficacy of the BoNT-A mixes with geltreatment.

Example 22

In order for the hydrogel formulation to be suitable for drug deliveryin the bladder it must comply with the natural physiological changes involume and shape i.e expansion during urine accumulation and contractionduring urine voiding. During its the physiological function the bladderexpends to about 5 times its original size. This property is tested foreach hydrogel composition in the manner described hereof:

The flexibility of one embodiment of the reverse thermal gelationhydrogel (DTC1) for drug delivery was tested in vitro using sheepbladder tissue. To investigate the effect of tissue tension/expansion onhydrogel coverage, DTC1 stained with methylene blue was layered on topof a the mucosal side of rectangle section of bladder tissue with anarea of 3*3 cm. Following hydrogel gelation the tissue was starched andexpanded by 3 fold to each direction (horizontally and vertically). Thereceived area was 9 fold larger than the initial surface tissue area.The hydrogel coverage of the tissue following tissue expansion wasexamined. The hydrogel was shown to follow the stretched tissue. No geldetachment was observed.

Example 23

An important feature that influences the hydrogel is its dissolutionrate/erosion rate. Therefore dissolution properties of hydrogelsdisclosed in the present invention composition were studied.

The dissolution rate was determined using an in-vitro membrane freedissolution model at 37° C. In this model the gel is dissolved into thereceptor medium (Dulbecco's phosphate buffer saline) which is carefullylayered on top of a smooth and flat gel layer. The amount of geldissolved is determined gravimetrically. After each sampling of thereceptor medium it is carefully discarded and replaced by a freshmedium.

Reference is now made to FIG. 8 , which presents the dissolution rate ofsix different hydrogels herein disclosed. The results demonstratedifferent dissolution rate of the various formulations tested. Thesevarious dissolution rates will determine the treatment durationfollowing instillation of the drug loaded hydrogel. Hence, the reversethermal gelation hydrogel composition for effective treatment of theurinary tract will be set based on the beneficial treatment duration forspecific disease.

Example 24

A further embodiment of the material disclosed in the present invention(DTC-11) is utilized upon organ linings consisting of serous tissue thatdoes not possess a mucosal layer, in particular pleural and peritonealwalls. A condition common in several lung and heart diseases is pleuraleffusion, when serous fluids, pus or chyle accumulate into the spacebetween the visceral pleura and the parietal pleura layers surroundingthe lungs—condition called also hydrothorax. Certain malignanciesenlarge the space between pleura layers and cause excessive levels offluids to accumulate and impair breathing. Standard treatments forpleural effusions is the insertion of intercostals drain, oftenaccompanied by surgical pleurodesis—in which the two pleural surfacesare scarred to each other so that no fluid can accumulate between them.Surgical joining of the layers is not always successful, but it ispermanent.

A material of the present invention can be administered into the pleuracavity to adhere to the pleura layers and provide both a mechanical bondand sustained release of drug for treatment of the underlying malignancy(e.g. Tetracycline antibiotic for bacterial infection, or NSAID such asNaproxen to treat fever and inflammation).

The pleura-hydrogel material is inserted into the pleura space via acatheter or trocar, as non-viscous liquid at a temperature that is below20° C. and adheres to the surrounding tissue as it heats to bodytemperature. The material is designed to dissolve gradually into thepleura fluids over less than a week and both maintain mechanical supportand release therapeutic agents during that whole period.

This procedure can replace the more invasive pleurodesis with theadditional benefits of tissue damage reduction, the soothing effect ofthe hydrogel and improved healing due to the sustained release ofanti-inflammatory agents.

The following exemplary formulation can be applied (DTC11):

PEG-PLGA-PEG* 24.5%  HPMC 0.1% PEG 400 0.4% DDW to 100%   *Ethyleneglycol-lactic acid-co-glycolic acid-ethylene glycol triblock copolymer

Said composition adheres well to said walls providing an effectivematrix for the transport and release of therapeutic active ingredients.In particular, the admixture can carry anti-inflammatory drugs to beapplied in case of pleural or peritoneal inflammation.

Example 25

Fixation of Organs and Prevention of Tissue Adhesion in the AbdomenDuring Laparoscopy:

A material of the current invention can be introduced into the abdomencavity and provide mechanical support to the target organs in theposition that best fits the surgical procedure. The peritoneum-hydrogelmaterial can be inserted into the peritoneum cavity via endoscopeworking channel, a catheter or trocar, as non-viscous liquid at atemperature that is below 15° C. and adhere to the surrounding tissue asit heats to body temperature. The material is designed to dissolvegradually into the pleura fluids over less than a week and both maintainmechanical support of the organs for several hours and release the drugsduring a longer period.

Similar method, but with different materials can be used to prevent theadhesion of tissues between organs in the treated area, which may oftenoccur during laparoscopic surgery.

The main advantages of this method are the combination of its ability toreplace a more invasive procedure, the reduction of tissue damage, thesoothing effect of the hydrogel and the enhanced healing effect of thesustained release of anti-inflammatory agents. A further advantage isthe prevention of the need to remove the fixation surgically because ofthe natural degradation and expelling of the invented material from thetreated area.

The following exemplary formulation can be applied (DTC-12):

PEG-PLGA-PEG* 24.5%  CMC 0.4% PEG 400 0.4% DDW to 100%  

Example 26

A binary API system (DTC-13 to DTC-16) was formulated which allowed adifferent release profile from the same gel structure. The relativerelease rate from the basic formulation was controlled by the additionof changing amounts of the surfactant sodium dodecyl sulfate (SDS),which affected the overall lipophilic/hydrophilic balance of theformulation. The APIs in question were mitomycin C (MMC) and lidocaine.The following table presents the composition of three basic formulationsand the release time of 80% of each of the two APIs. From an applicativepoint of view, it is of much interest to obtain a relatively rapidrelease of lidocaine, which produces the local anesthetic effect uponthe organ tissue to be treated, followed by a slow release of the MMC,that may allow a superior chemotherapeutic treatment of said organ.

TABLE 11 MATERIAL DTC-13 DTC-14 DTC-15 DTC-16 Pluronic F127 (%) 27.027.0 27.0 27.0 HPMC (%) 0.2 0.2 0.2 0.2 PEG-400 (%) 1.0 1.0 1.0 1.0 SDS(%) 0 0.05 0.1 0.2 DDW (%) 71.8 71.75 71.7 71.6 MMC (%) 0.1 0.1 0.1 0.1Lidocaine (%) 1.0 1.0 1.0 1.0 Release time 80% 16 15 14 12 MMC (hrs)Release time 80% 180 120 60 10 Lidocaine (min)

The results shown in table 11 demonstrate that adding a small amount ofSDS dramatically affects the release profile of the two drugsrespectively. This exemplifies, without limiting, the possibilities ofengineering the gel composition in a way that allows two or moredifferent APIs to release from the gel matrix each at their ownpace—according to the treatment needs. In the example above, it may bedesirable, for example, that the soothing effect of the lidocaine befelt by the patient rapidly, just before the MMC commences its ownactivity, that may be painful, and thus a rapid release of the lidocainemay be desired while a slow release of the same may be unfelt and thisineffective. On the other hand, one can conceive other treatments wherea lower but more prolonged anesthetic effect be required, and thus theformulation will change accordingly. The possibilities are limitless aspresented by the non-limiting examples above.

Example 27

Prior to testing the efficacy of botulinum toxin (BTX) incorporated intoGel A as a treatment for bladder disorders characterized by bladderspasms, the activity of BTX in the gel and following release from thegel was confirmed.

The activity of BTX was determined using single intramuscular (IM)administration of test items to mice (Hsd:ICRFemale), similar to themethod disclosed in Aoki, K. R., “A Comparison of the Safety Margins ofBotulinum Neurotoxin Serotypes A, B, and F in Mice”, Toxicol. 2001, 39,1815-1820, the contents of which are hereby incorporated by reference intheir entirety. The effect of commercially available BTX-A solubilizedin saline or gels, or released from gels by saline on the local muscleweakening was compared (saline injection served as negative control).Test animals were injected at a dose of about 20 U/kg body weight at adose volume of 10 μl per animal to the right hind limb. A DigitAbduction Assay (DAS) was used to determine the local muscle weakeningefficacy 48 hours after dosing. The DAS scoring was carried out bybriefly suspending the animal by its tail to elicit a characteristicstartle-response, namely causing the animal to extend its hind-limbs andabduct its respective hind digits. Reference is now made to FIG. 9 ,which depicts schematically the 5-point scale used to score the relativeextent of BTX-A induced muscular paresis. According to this scale, ascore of 0 represents a normal response, while a score of 4 representsthe maximal reduction in digit abduction. The left column in FIG. 9illustrates the scale for an untreated left hind leg, and the rightcolumn illustrates the scale for a treated right hind leg. The resultsare summarized in Table 12.

TABLE 1 Test results of BTX activity following intramuscular injectionRight hind leg Left hind leg (treated) (untreated) Group Average Average(n = 10) score SD score SD Saline-control 0 0 0 0 BTX in saline 2.5 0.970 0 BTX in Gel A 2.3 1.06 0 0 BTX release from Gel A 2.3 1.06 0 0 BTXrelease from Gel A 2.3 1.25 0 0 BTX release from Gel A, 3 1.05 0 0 pHadjusted to 5.2

The results demonstrate that the activity of BTX injected in Gel A orreleased from Gel A is similar to that of BTX in saline. A slightincrease in the activity was observed for BTX release from Gel A thatwas pH adjusted (With HC1) to 5.2 (within the test SD). Low pH is knownin the literature to promote BTX stability. Hence BTX administered tothe bladder in Gel A (or similar gel formulations) is expected topreserve its biological activity within the gel and following itsrelease from the gel. Moreover the gel is expected to increase BTXstability within the bladder by preserving its three dimensionalstructure and adjusting its surrounding conditions (as pH) in order toensure its maximal stability during instillation.

Example 28

The enhanced effect of BTX following mixing with TheraCoat systems fortreatment of bladder disorders was demonstrated in a bladder cystitisrat model. The testing method is described in Chuang, Y. C.; Yoshimura,N.; Huang, C. C.; Wua, M. “Intravesical Botulinum Toxin A AdministrationInhibits COX-2 and EP4 Expression and Suppresses Bladder Hyperactivityin Cyclophosphamide-Induced Cystitis in Rats,” Eur. Urol. 2008, 56,159-167, which is hereby incorporated by reference in its entirety.Chronic cystitis was induced by intraperitoneal injection ofcyclophosphamide (75 mg/kg was injected on day 1, 4 and 7). On day two,polyethylene tubing (PE-50) was inserted into the rat bladder throughthe urethra. The bladder was drained and instilled with gel or salinewith and without BTX (1 ml, 20 u/ml Allergan). On day 8 the animal wasanesthetized and the bladder was examined by data requisition POWER LABvia millar transducer inserted into the bladder dome. After recoveryfrom anesthesia the animal was gently restrained and the suprapubiccatheter was connected to infusion pump (0.08 ml/min continuously) andpressure transducer for recording of intravesical pressure and forsaline infusion into the bladder in order to elicit repetitive voiding.The amplitude and the inter-contraction interval of reflex bladdercontractions were recorded. Each treatment group comprised 2-4 animals.

Reference is now made to FIGS. 2A-2B, which present graphs summarizingthe amplitude (FIG. 2A) and inter-contraction interval (FIG. 2B) of ratbladder in control experiments in which the rats were treated withsaline or a gel formulation not containing any therapeutic agent.Similar results were obtained for all treatments, suggestion that thegel formulations without BTX have no effect on the bladder. Reference isnow made to FIGS. 10A-10B, which presents graphs of contractionamplitude (FIG. 10A) and inter-contraction interval (FIG. 10B) followinginduction of bladder hyperactivity by intraperitoneal injection ofcyclophosphamide (CYP). The bladder hyperactivity, as shown by acomparison of results for rats treated with CYP and saline to those forthe control group treated by saline alone, is characterized by anincrease in contraction amplitude and decrease in inter contractioninterval. Rats that were administered with BTX reconstituted in salineor in gel formulations were shown to suppress the cyclophosphamideeffect by decrease of contraction amplitude and increase ofinter-contraction intervals. As shown in the figure, treatment by BTXincorporated into any one of the four gel formulations tested has agreater effect than treatment with BTX reconstituted in saline.

What is claimed is:
 1. A method of providing sustained-release topicaltreatment of a condition affecting an internal body cavity, the methodcomprising administering a pharmaceutical composition comprising athermoreversible hydrogel to an internal body cavity of the urinarytract, wherein the thermoreversible hydrogel comprises an activepharmaceutical ingredient, wherein the method comprises controlledrelease of the active pharmaceutical ingredient, wherein, afteradministration, the concentration of the active pharmaceuticalingredient in urothelium of the internal body cavity is increased whencompared to the concentration of the active pharmaceutical ingredient inurothelium of the internal body cavity following administration of acontrol composition comprising the same dose and concentration of activepharmaceutical ingredient in water.
 2. The method of claim 1, whereinthe concentration of the active pharmaceutical ingredient is increased 2hours after the administration of the pharmaceutical composition.
 3. Themethod of claim 1, wherein the concentration of the activepharmaceutical ingredient is increased 6 hours after the administrationof the pharmaceutical composition.
 4. The method of claim 1, wherein theconcentration of the active pharmaceutical ingredient followingadministration of the pharmaceutical composition is at least 11-foldhigher than the concentration of the active pharmaceutical ingredientfollowing administration of the control composition.
 5. The method ofclaim 1, wherein the thermoreversible hydrogel has a gel pointtemperature of about 10° C. to about 37° C.
 6. The method of claim 1,wherein the thermoreversible hydrogel has a gel point temperature ofabout 4° C. to about room temperature.
 7. The method of claim 1, whereinthe thermoreversible hydrogel has a gel point temperature of about 12°C. to about 22° C.
 8. The method of claim 1, wherein thethermoreversible hydrogel has a gel point temperature of about 14° C.,about 15° C., or about 17° C.
 9. The method of claim 1, wherein thethermoreversible hydrogel has a gel point temperature of about 12° C. toabout 17° C.
 10. The method of claim 1, wherein the thermoreversiblehydrogel has a gel point below 20° C.
 11. The method of claim 1, whereindelivery of the thermoreversible hydrogel results in sustained releaseof the active pharmaceutical ingredient for at least 2 hours, at least 6hours, at least 12 hours, at least 16 hours, at least 18 hours, over12-24 hours, over 16-24 hours, or over 24 hours.
 12. The method of claim1, wherein the active pharmaceutical ingredient is selected from thegroup consisting of antineoplastic drugs; chemotherapeutic agents;anti-infective agents, antimicrobial drugs, antiparasitic agents,antivirals; drugs acting on the blood and blood forming organs,antihemorrhagics, antithrombotic agents, antianemia drugs, dermatologicdrugs, antifungals, antiseptics, genito-urinary system drugs,gastrointestinal system drugs, antiobesity drugs, drugs for treatingacid related disorders, metabolism drugs, anti-inflammatory product,musculoskeletal system acting drugs; neurological drugs, respiratorydrugs, gene therapy, cardio-vascular drugs, otological drugs,corticosteroids, analgesic and anesthetic drugs, growth factors,vascular endothelial growth factor (VEGF), inhibitory factors,interleukin 6 class cytokine (LIF) and any combination thereof.
 13. Themethod of claim 1, wherein the active pharmaceutical ingredient isselected from the group consisting of Mitomycin C, Deoxrubicin,Valrubicin, Gemcitabine, Thiotepa, Taxotere, Ethoglucid (Epodyl),Epirubicin, Pirarubicin, Apaziquone, Vicinium, Botulinum toxin,Lidocaine, Naproxen, Ibuprofen and combinations thereof.
 14. The methodof claim 1, wherein the active pharmaceutical ingredient is aantineoplastic drug, a chemotherapeutic agent, or a combination thereof.15. The method of claim 1, wherein the active pharmaceutical ingredientis Mitomycin C.
 16. The method of claim 9, wherein the activepharmaceutical ingredient is mitomycin C.
 17. The method of claim 1,wherein the hydrogel is gradually diluted and expelled from the bodywithin 24 hours after administration.
 18. The method of claim 1,wherein: a) the thermoreversible hydrogel has a gel point temperature ofabout 4° C. to about room temperature; b) the hydrogel is graduallydiluted and expelled from the body within 24 hours after administration;and c) the thermoreversible hydrogel has a pH of 5.5-8.0.
 19. The methodof claim 18, wherein the active pharmaceutical ingredient is mitomycinC.
 20. The method of claim 18, wherein the thermoreversible hydrogel hasa gel point temperature of about 12° C. to about 17° C.
 21. The methodof claim 18, wherein the active pharmaceutical ingredient is mitomycin Cand the thermoreversible hydrogel has a gel point temperature of about12° C. to about 17° C.
 22. The method of claim 18, wherein the internalbody cavity is an upper urinary tract, urinary bladder, renal pelvis,kidney, or any combination thereof.
 23. The method of claim 18, whereinthe internal body cavity is a kidney.
 24. The method of claim 18,wherein the internal body cavity is a urinary bladder.
 25. The method ofclaim 1, wherein the condition affecting an internal body cavity is acancer.
 26. The method of claim 1, wherein the condition affecting aninternal body cavity is a urinary tract cancer.
 27. The method of claim1, wherein the condition affecting an internal body cavity is acarcinoma of the upper urinary tract, transitional cell carcinoma in theupper urinary tract, urothelial carcinoma, urothelial carcinoma of therenal pelvis and ureter, ureteral cancer, bladder cancer, renal cancer,or any combination thereof.
 28. The method of claim 1, wherein thecondition affecting an internal body cavity is a bladder cancer.
 29. Themethod of claim 1, wherein the internal body cavity is a kidney and thecondition affecting an internal body cavity is upper urinary tracttransitional cell carcinoma.
 30. The method of claim 1, wherein theinternal body cavity is a urinary bladder and the condition affecting aninternal body cavity is bladder cancer.
 31. The method of claim 29,wherein the active pharmaceutical ingredient is mitomycin C.
 32. Themethod of claim 30, wherein the active pharmaceutical ingredient ismitomycin C.
 33. The method of claim 1, wherein the thermoreversiblehydrogel has a pH of 5.5-8.0.
 34. The method of claim 18, wherein thepharmaceutical composition has two or more of the following: a viscosityof less than 5 Pa·s over a temperature range of 4° C.-12° C.; aviscosity of greater than 10³ Pa·s at 37° C.; a peel strength of 0.5-5.0N·cm⁻² tested using ASTM D2256-03 at 37° C.; and a flexibility such thata 3 cm×3 cm section of bladder tissue layered with the thermoreversiblehydrogel at room temperature can be stretched to 9 cm×9 cm withoutdetachment of the thermoreversible hydrogel from the bladder tissue. 35.The method of claim 18, wherein the thermoreversible hydrogel comprisesa poloxamer.
 36. The method of claim 35, wherein the poloxamer isPoloxamer
 407. 37. The method of claim 18, wherein the thermoreversiblehydrogel comprises an ethylene oxide/propylene oxide triblock copolymer.38. A pharmaceutical composition for providing sustained-release topicaltreatment of a condition affecting an internal body cavity of theurinary tract, comprising a thermoreversible hydrogel; and an activepharmaceutical ingredient; wherein the thermoreversible hydrogel iscapable of effecting controlled release of the active pharmaceuticalingredient in the internal body cavity of the urinary tract, wherein,after administration, the concentration of the active pharmaceuticalingredient in urothelium of the internal body cavity is increased whencompared to the concentration of the active pharmaceutical ingredient inurothelium of the internal body cavity following administration of acontrol composition comprising the same dose and concentration of activepharmaceutical ingredient in water.
 39. The pharmaceutical compositionof claim 38, wherein the concentration of the active pharmaceuticalingredient is increased 2 hours after the administration of thepharmaceutical composition.
 40. The pharmaceutical composition of claim38, wherein the concentration of the active pharmaceutical ingredient isincreased 6 hours after the administration of the pharmaceuticalcomposition.
 41. The pharmaceutical composition of claim 38, wherein theconcentration of the active pharmaceutical ingredient followingadministration of the pharmaceutical composition is at least 11-foldhigher than the concentration of the active pharmaceutical ingredientfollowing administration of the control composition.
 42. Thepharmaceutical composition of claim 38, wherein: a) the thermoreversiblehydrogel has a gel point temperature of about 4° C. to about roomtemperature; b) the hydrogel is gradually diluted and expelled from thebody within 24 hours after administration; and c) the thermoreversiblehydrogel has a pH of 5.5-8.0.
 43. The pharmaceutical composition ofclaim 38, wherein the active pharmaceutical ingredient is selected fromthe group consisting of antineoplastic drugs; chemotherapeutic agents;anti-infective agents, antimicrobial drugs, antiparasitic agents,antivirals; drugs acting on the blood and blood forming organs,antihemorrhagics, antithrombotic agents, antianemia drugs, dermatologicdrugs, antifungals, antiseptics, genito-urinary system drugs,gastrointestinal system drugs, antiobesity drugs, drugs for treatingacid related disorders, metabolism drugs, anti-inflammatory product,musculoskeletal system acting drugs; neurological drugs, respiratorydrugs, gene therapy, cardio-vascular drugs, otological drugs,corticosteroids, analgesic and anesthetic drugs, growth factors,vascular endothelial growth factor (VEGF), inhibitory factors,interleukin 6 class cytokine (LIF) and any combination thereof.
 44. Thepharmaceutical composition of claim 38, wherein the activepharmaceutical ingredient is selected from the group consisting ofMitomycin C, Deoxrubicin, Valrubicin, Gemcitabine, Thiotepa, Taxotere,Ethoglucid (Epodyl), Epirubicin, Pirarubicin, Apaziquone, Vicinium,Botulinum toxin, Lidocaine, Naproxen, Ibuprofen and combinationsthereof.
 45. The pharmaceutical composition of claim 38, wherein theactive pharmaceutical ingredient is a antineoplastic drug, achemotherapeutic agent, or a combination thereof.
 46. The pharmaceuticalcomposition of claim 38, wherein the active pharmaceutical ingredient isMitomycin C.
 47. The pharmaceutical composition of claim 42, wherein theactive pharmaceutical ingredient is mitomycin C.
 48. The pharmaceuticalcomposition of claim 42, wherein the thermoreversible hydrogel has a gelpoint temperature of about 12° C. to about 17° C.
 49. The pharmaceuticalcomposition of claim 42, wherein the active pharmaceutical ingredient ismitomycin C and the thermoreversible hydrogel has a gel pointtemperature of about 12° C. to about 17° C.